Loteprednol and moxifloxacin compositions and methods

ABSTRACT

Provided here are new ophthalmologically suitable pharmaceutical compositions comprising an effective amount of a moxifloxacin compound and an effective amount of a loteprednol compound. In aspects, the compositions are stable suspensions, which maintain physical stability and chemical stability for extended periods of time (e.g., exhibiting no sustained flocculation, coagulation, or clumping after several months of storage under typical storage conditions). In aspects, the compositions are suspensions that include a suspension component comprising one or more suspension agents. In aspects, the suspension component includes an ionic suspension agent. In aspects, the composition also or alternatively comprises a non-ionic surfactant, non-ionic suspension agent, or both, or an agent that provides both functions. In aspects, such compositions further comprise an effective amount of a chelating agent/component. Further described are related compositions and methods of making and using such compositions, e.g., in the treatment of eye infections.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent Applications claims priority to U.S. Provisional PatentApplication No. 63/070,529, filed Aug. 26, 2020, entitled “Moxifloxacinand Prednisolone Ophthalmic Suspension.” This application claims thebenefit of priority to, and incorporates by reference the entirety of,this above-referenced priority application.

FIELD OF THE INVENTION

The invention relates to compositions or methods for the treatmentophthalmological conditions, such as bacterial infections of the eye.

BACKGROUND OF THE INVENTION

It is estimated that 80% of what a typical human perceives comes throughthe sense of sight. Accordingly, humans place a remarkable value onvision. In fact, reportedly 88% of participants in one study rankedvision as their most valued sense.

According to the American Academy of Ophthalmology, “Visual impairmentis a . . . national health concern that has a negative impact onphysical and mental health.” Unfortunately, there are a number ofmedical conditions that threaten good eye health. For example, WebMDdescribes 19 “common” eye ailments. Some of these conditions, likeglaucoma, impact millions of people per year. For example,conjunctivitis of the eye (e.g., pink eye), which can be caused by viralor bacterial infections, impacts an estimated six million Americansannually. Bacterial infections are considered one of the most commontypes of eye disorders. Such ophthalmic infections are frequentlyaccompanied by inflammation of the infected ophthalmic tissues andsometimes the surrounding tissues. Similarly, ophthalmic surgicalprocedures that pose a risk of microbial infections may also causeinflammation of the affected tissues.

Disorders of the eye, such as bacterial infections of the eye, can leadto the need for application of pharmaceutical treatments, ocularsurgical procedures, or both. Examples of these ophthalmic surgicalprocedures include cataract or lens replacement surgery. Given suchfacts, it is perhaps not surprising that an estimated 39 billion dollarswas spent on treatments for conditions of the eye in 2021. The globalmarket for conjunctivitis treatments alone is expected to exceed 6.5billion dollars by the end of the decade. A large number of treatmentshave been approved over the last several decades to deal with bacterialconjunctivitis, including application of various aminoglycosides (e.g.,tobramycin, gentamycin, etc.), macrolides (e.g., erythromycin, etc.),and use of other agents such as bacitracin, neomycin, polymyxin,sulfacetamide, chloramphenicol, fusidic acid, povidone-iodine, as wellas a number of 2^(nd), 3^(rd), and 4^(th) generation fluoroquinoloneantibiotics.

The quinolone antibiotics were developed in the early 1960s. Nalidixicacid is considered to be the predecessor of all members of the quinolonefamily, including the fluoroquinolones. Since the introduction ofnalidixic acid, reportedly more than 10,000 quinolone analogs have beensynthesized, but only a handful of such compounds have found their wayinto clinical practice. Some quinolone antibiotic compositions areeffective in treating ophthalmic infections and have distinct advantagesover prior ophthalmic antibiotic compositions, particularly those havingrelatively limited spectrums of antimicrobial activity. For example,neomycin, polymyxin B, gentamicin and tobramycin are primarily usefulonly against gram negative bacteria while bacitracin, gramicidin, anderythromycin are primarily useful only against gram positive bacteria.This well-known disparity in effectiveness reflects just some of theways that quinolone antibiotics can vary in terms of pharmaceuticalproperties. For example, while FDA approved quinolone antibioticproducts are useful for ophthalmologic and non-ophthalmologicapplications, this is not always the case. In 2006, Bristol-Myers Squibbremoved its gatifloxacin from the market after significant development,and sales of $150 million in 2005, due to safety concerns, despite thefact that ophthalmic gatifloxacin is considered well tolerated and hasremained on the market since its launch in 2010 (marketed under thetradename Zymaxid®—Allergan).

Quinolones were widely used as a first-line treatment for manyinfections, including very commons ones such as acute sinusitis, acutebronchitis, and uncomplicated UTIs. Beginning in 2003, the topicalocular fourth-generation fluoroquinolones, moxifloxacin andgatifloxacin, were approved for treating bacterial conjunctivitis. Theseantibiotics represent the most advanced group of compounds within theclass, offer a unique dual-binding mechanism of action in gram-positiveorganisms, and have activity against otherwise resistant species.However, reports of serious adverse events began emerging in the 2000s,and the FDA first added a “black box” warning to fluoroquinoloneproducts in July 2008 for the increased risk of tendinitis and tendonrupture. In February 2011, the risk of worsening symptoms for those withmyasthenia gravis was added to the warning. In August 2013, the agencyrequired updates to the labels to describe the potential forirreversible peripheral neuropathy (serious nerve damage). In November2015, an FDA Advisory Committee discussed the risks and benefits offluoroquinolones for the treatment of acute bacterial sinusitis, acutebacterial exacerbation of chronic bronchitis, and uncomplicated UTIsbased on new safety information. The new information focused on two ormore side effects occurring at the same time and causing the potentialfor irreversible impairment. The FDA advisory committee concluded thatthe serious risks associated with the use of fluoroquinolones for thesetypes of uncomplicated infections generally outweighed the benefits forpatients with other treatment options, resulting in a recommendation ofstronger safety warnings and more FDA safety communications regardingsuch drugs in 2016. There are also growing concerns about the use ofthese products due to the potential for developing antibiotic-resistantstrains.

In addition to the serious concerns surrounding fluroquinoloneantibiotics as active pharmaceutical ingredients (“APIs”), treatingconditions of the eye, generally, is particularly challenging for thehealth care industry. For example, between 2003-2014, more than 14pharmaceutical companies unsuccessfully attempted to secure FDA approvalfor dry eye drugs. Ocular tissue is one of the most complex andsensitive tissues in the human body. Accordingly, ophthalmologicalformulations can have a significant impact on the efficacy of suchproducts. For example, the efficacy of many ophthalmological topicalapplications, such as, for example, those attempting to treat eyeconditions such as conjunctivitis (inflammation of the conjunctiva) orother external ocular infections, often hinges on their ability tomaintain contact with the afflicted eye anatomy or be retained by theeye, e.g., permeate and be held within, the cornea. Several excipientsthat are suitable for other types of pharmaceuticals or food are notsuitable for ophthalmological applications (e.g., preservatives such asparabens, chlorocresol, and other agents are often not consideredsuitable for ophthalmological use). Moreover, changes to a singleingredient in ophthalmic formulations comprising even the same API canhave significant effects on the pharmaceutical properties of such aformulation. For example, LUMIGAN® 0.01%, comprising one third theamount of the ophthalmological active ingredient bimatoprost,surprisingly shows very similar efficacy to LUMIGAN® 0.03%, despite onlycontaining one-third of the active pharmaceutical ingredient (“API”),due to an increase in concentration of a single non-active excipient inthe drug formulation (benzalkonium chloride). Even FDA-approved genericophthalmologic products can be associated with significant challengesdue to formulation issues. For example, with respect to prednisoloneacetate 1% formulations, the generic formulation has exhibited caking ofthe drug and inadequate suspension of the product constituents, possiblycompromising the treatment of inflamed eyes. Fiscella, Review ofOptometry, 2002. Complaints of precipitated product clogging of thedropper tip have been filed, and two lots of generic prednisoloneacetate were recalled due to precipitation of the active ingredient. Id.

The quinolones have properties that also require special attention withrespect to drug product formulation. For example, published studiesregarding the corneal penetration of fluoroquinolone products reflectthat such products can exhibit different levels of penetration (e.g.,with some studies demonstrating that on-market moxifloxacin andgatifloxacin products significantly greater levels in the aqueous humorthan on-market ciprofloxacin product). Other studies have shown similardisparities in concentrations of other fluoroquinolone APIs fromon-market formulations. Products containing multivalent cations, such asaluminum- or magnesium-containing antacids, and products containingcalcium, iron, or zinc interact with fluoroquinolones and reduce drugefficacy. Other reactants with such APIs include sucralfate, probenecid,cimetidine, theophylline, warfarin, antiviral agents, phenytoin,cyclosporine, rifampin, pyrazinamide, and cycloserine.

There is a long history in patent records of attempts to address suchproblems with respect to fluroquinolone formulations. For example, U.S.Pat. No. 6,333,045 B1, which issued nearly 20 years ago, discloses, as atechnique of enhancing cornea permeability of a drug, an aqueous liquidpreparation containing gatifloxacin or a salt thereof at a relativelylow concentration of gatifloxacin of lower than 0.5 w/v %, and sodiumedetate at a low concentration. Furthermore, it reports that thesolubility of gatifloxacin can be increased and precipitation ofgatifloxacin crystals can be prevented in an aqueous liquid preparationcontaining gatifloxacin at a relatively low concentration of lower than0.5 w/v % or a salt thereof by adding sodium edetate.

Many of the other formulations described in the patent literature focuson the use of xanthan gum. For example, U.S. Pat. No. 6,331,540 B1discloses a pharmaceutical composition containing a fluoroquinoloneantibiotic drug, xanthan gum and a water-soluble calcium salt. U.S.Publication No. 2009/0247543 A1 similarly discloses an aqueous liquidpreparation comprising gatifloxacin or a pharmacologically acceptablesalt thereof or a hydrate thereof, phosphoric acid or a salt thereof,and xanthan gum, wherein a pH thereof is 5.5 or more and less than 7.0.The suggested use of xanthan gum has been adopted in the art, with bothmoxifloxacin (e.g., Moxeza®—Novartis) and on-marketmoxifloxacin/tobradex eye drop formulations containing xanthan gum.

U.S. Patent Publication No. 2014/0213561 A1 discloses a topicalophthalmic composition for treating ophthalmic bacterial infections in ahuman patient wherein the ophthalmic composition comprising gatifloxacinand prednisolone. The disclosed suspending agent in ophthalmiccompositions disclosed in this patent publication includes METHOCEL™ F4M(a medium molecular weight hydroxypropyl methylcellulose (HPMC)thickener). Although Avelox IV is an intravenous formulation comprisingmoxifloxacin and microcrystalline cellulose, leading fluroquinoloneophthalmology formulations do not appear to have implemented thesuggestion to use cellulose suspension agents.

These earlier products appear to be associated with shortcomings interms of formulation properties, leading to the more recent suggestionto use other suspension agents, particularly non-ionicpolyoxyethylene-polyoxypropylene block copolymer suspension agents(e.g., poloxamer suspension agents such as Pluronic® F-127 (BASFCorporation) and Poloxamer-407 (BASF Corporation)), to overcome suchissues. For example, U.S. Patent Publication No. 2015/0024996 A1discloses pharmaceutical compositions for intraocular administrationcomprising an anti-bacterial agent and anti-inflammatory agent, anexcipient that acts as both a suspending agent and a solubilizing agent.The '996 application only cites non-ionicpolyoxyethylene-polyoxypropylene block copolymers as providing such afunction. The anti-bacterial agent selected from quinolone, afluorinated quinolone, and pharmaceutically acceptable salts, hydrates,solvates, or N-oxides thereof and the anti-inflammatory agent selectedfrom corticosteroids and pharmaceutically acceptable salts, hydrates,solvates, ethers, esters, acetals, and ketals thereof. U.S. PatentPublication No. 2019/0105320 A1 similarly discloses pharmaceuticalcompositions that include an anti-bacterial agent such as moxifloxacinand an anti-inflammatory agent such as prednisolone for intraocularinjection. Both publications identify moxifloxacin as creatingdifficulties in forming stable suspension compositions when anothercomponent such as a corticosteroid like triamcinolone acetonide ispresent in the same formulation. These publications explain that thestable suspension problem is a result of moxifloxacin's tendency todeactivate many suspending agents, making unacceptable coagulation,clumping and flocculation. These publications also explain that numerousattempts by others to address this problem have been failed but theinventors were successful under specific conditions, namely by using anon-ionic polyoxyethylene-polyoxypropylene block copolymer at an amountof up to 10% by mass. The publication does not provide a differentexcipient that provides a stable composition with moxifloxacin orgatifloxacin and a corticosteroid such as triamcinolone acetonide.

As can be seen from the foregoing, in view of the sensitive and complexnature of the eye and the numerous known challenges in formulatingophthalmological products, particularly fluroquinolone formulations,inventive approaches are required to develop new effectivefluroquinolone ophthalmological products that exhibit desirableproperties such as reduced inflammation risk, uniform API distribution,and API stability.

Construction, Terms, and Acronyms

This section offers guidelines for reading this disclosure. The intendedaudience for this disclosure (“readers”) are persons having ordinaryskill in the practice of technologies discussed or used herein. Readersmay also be called “skilled persons,” and such technologies called “theart.” Terms such as “understood,” “known,” and “ordinary meaning,” referto the general knowledge of skilled persons.

The term “uncontradicted” means not contradicted by this disclosure,logic, or plausibility based on knowledge of skilled persons.

Disclosed here are several different but related exemplary aspects ofthe invention (“aspects”) (“cases,” “facets,” or “embodiments”). Theinvention encompasses all aspects, as described individually and as canbe arrived at by any combination of such individual aspects. The breadthand scope of the invention should not be limited by any exemplaryembodiments. No language in this disclosure should be construed asindicating any element/step is essential to the practice of theinvention unless such a requirement is explicitly stated.Uncontradicted, any aspect(s) can be combined with any other aspect(s).

Uncontradicted, all technical/scientific terms used here generally havethe same meanings as commonly understood by skilled persons, regardlessof any narrower examples or descriptions provided here (including anyterm introduced initially in quotations). However, aspects characterizedby the inclusion of elements, steps, etc., associated with specificdescriptions provided here are distinct embodiments of the invention.Uncontradicted, disclosure of any aspect using known terms, which termsare narrowed by example or otherwise in this disclosure, implicitlydiscloses related aspects in which such terms are alternativelyinterpreted using the broadest reasonable interpretation of skilledpersons.

Uncontradicted, “or” means “and/or” here, regardless of any occasionalinclusion of “and/or” (e.g., phrases such as “A, B, or C” and “A, B,and/or C” simultaneously disclose aspects including (1) all of A, B, andC; (2) A and C; (3) A and B; (4) B and C; (5) only A; (6) only B; and(7) only C (and also support sub-groupings, such as “A or B,” “A or C,”etc.)).

Uncontradicted, “also” means “also or alternatively.” Uncontradicted,“here” & “herein” mean “in this disclosure”. The term “La.” (“ia” or“ia”) means “inter alia” or “among other things.” Uncontradicted,“elsewhere” means “elsewhere herein.”

For conciseness, symbols are used where appropriate. E.g., “&” is usedfor “and,” & “˜” for “about.” Symbols such as < and > are given theirordinary meaning (e.g., “≤” means “less than or equal to” & “>” means“greater than or equal to”). A slash “/” can represent “or” (“A/B” means“A or B”) or identify synonyms of an element, as will be clear fromcontext.

The inclusion of “(s)” after an element or a step indicates that ≥1 ofsuch an element is present, step performed, and the like. E.g.,“element(s)” means both 1 element or ≥2 elements, with the understandingthat each thereof is an independent aspect of the invention.

Use of the abbreviation “etc.” (or “et cetera”) in association with alist of elements/steps means any or all suitable combinations of therecited elements/steps or any known equivalents of such recitedelements/steps for achieving the function(s) of such elements/steps thatare known in the art. Terms such as “and combinations,” or “orcombinations” regarding listed elements/steps means combinations of anyor all such elements/steps. “Suitability” typically means acceptable orappropriate for performing a particular function/achieving particularstate(s)/outcome(s), and typically means effective, practical, andnon-deleterious/harmful in the context the term is used. “Pharmaceuticalsuitability”, “pharmaceutically suitable”, “ophthalmologically suitable”or “ophthalmological suitability” are phrases typically used to refer tocompositions that are safe and effective for pharmaceuticaladministration and application, having sufficient potency, purity,strength, quality, and safety for pharmaceutical application, in casesspecifically to the eye, as may be judged by regulatory authorityreview, and as established by, e.g., one or more well controlled andadequate clinical studies performed in compliance with generallyprevailing regulatory authority standards. Compositions described as“ophthalmologically suitable” should be interpreted to mean suitable forophthalmic delivery when provided in a potency, purity, strength, orquality making it safe for ophthalmic use. Components described as“ophthalmologically suitable” should be interpreted in a similar manner.Uncontradicted, a description of “suitability” implicitly means that thereferenced element, step, etc., is ophthalmologically/pharmaceuticallysuitable or otherwise medically suitable (e.g., safe and effective asdetermined by proper nonclinical/clinical testing).

Uncontradicted, heading(s) (e.g., “Construction, Terms . . . ”) andsubheadings are included for convenience and do not limit the scope ofany aspect(s). Uncontradicted, aspect(s), step(s), or element(s)described under one heading can apply to other aspect(s) orstep(s)/element(s) here.

Ranges of values are used to represent each value falling within suchrange that are within an order of magnitude of the smallest endpoint ofthe range without having to explicitly write each value of the range.E.g., a recited range of 1-2 implicitly discloses each of 1.0, 1.1, 1.2,. . . 1.9, and 2.0 and 10-100 implicitly discloses each of 10, 11, 12, .. . 98, 99, and 100). Uncontradicted, all ranges include the range'sendpoints, regardless of how a range is described. E.g., “between 1-5”includes 1 and 5 in addition to 2, 3, and 4 (and all numbers betweensuch numbers within an order of magnitude of such endpoints, e.g., 1.0,1.1, . . . 4.9, and 5.0). For the avoidance of doubt, any number withina range, regardless of the order of magnitude of the number, is coveredby the range (e.g., a range of 2-20 covers 18.593).

Terms of approximation (e.g., “about,” “˜,” or “approximately”) are used(1) to refer to a set of related values or (2) where a precise value isdifficult to define (e.g., due to limits of measurement).Uncontradicted, all exact values provided here simultaneously/implicitlydisclose corresponding approximate values and vice versa (e.g.,disclosure of “about 10” provides explicit support for the use of 10exactly in such aspect/description). Ranges described with approximatevalue(s) include all values encompassed by each approximate endpoint,regardless of presentation (e.g., “about 10-20” has the same meaning as“about 10-about 20”). The scope of value(s) encompassed by anapproximate term typically depends on the context of the disclosure,criticality or operability, statistical significance, understanding inthe art, etc. In the absence of guidance here or in the art, terms suchas “about” should be interpreted as +/−10% of the indicated value(s).

Lists of aspects, elements, steps, and features are sometimes employedfor conciseness. Unless indicated, each member of each list should beviewed as an independent aspect. Each aspect defined by any individualmember of a list can have, and often will have, nonobvious propertiesvis-a-vis aspects characterized by other members of the list.

Uncontradicted, the terms “a” and “an” and “the” and similar referentsencompass both the singular and the plural form of the referencedelement, step, or aspect. Uncontradicted, terms in the singularimplicitly convey the plural and vice versa herein (in other words,disclosure of an element/step implicitly discloses corresponding use ofsuch/similar elements/steps and vice versa). Hence, e.g., a passageregarding an aspect including X step supports a corresponding aspectincluding several X steps. Uncontradicted, any mixed use of a referentsuch as “a” in respect of one element/step or characteristic and “one ormore of” with respect to another element/step or characteristic in aparagraph, sentence, aspect, or claim, does not change the meaning ofsuch referents. Thus, for example, if a paragraph describes acomposition comprising “an X” and “one or more Ys,” the paragraph shouldbe understood as providing disclosure of “one or more Xs” and “one ormore Ys.”

“Significant” and “significantly” mean results/characteristics that arestatistically significant using ≥1 appropriate test(s)/trial(s) in thegiven context (e.g., p≤0.05/0.01). “Detectable” means measurablypresent/different using known detection tools/techniques. The acronym“DOS” (or “DoS”) means “detectable(ly) or significant(ly).”

Uncontradicted, for any value here that is not accompanied by a unit ofmeasurement (e.g., a weight of 50), any previously provided unit for thesame element/step or the same type of element/step will apply, or, incases where no such disclosure exists, the unit most commonly used inassociation with such an element/step in the art will apply.

Uncontradicted, the terms “including,” “containing,” “comprising,” and“having” mean “including, but not limited to” or “including, withoutlimitation.” Uncontradicted, use of terms such as comprising andincluding regarding elements/steps means including any detectable numberor amount of an element or including any detectable performance of astep/number of steps (with or without other elements/steps).

For conciseness, description of an aspect “comprising” or “including” anelement, with respect to a collection/whole (e.g., a system, device, orcomposition), implicitly provides support for any detectableamount/number or ≥˜1%, ≥˜5%, ≥˜10%, ≥˜20%, ≥˜25%, ≥˜33%, ≥˜50%, ≥˜51%,≥˜66%, ≥˜75%, ≥˜90%, ≥˜95%, ≥˜99%, or ˜100% of the whole/collectionbeing made up of the element, or essentially all of the whole/collectionbeing made up of the element (i.e., that the collection consistsessentially of the referenced element). Similarly, a method described asincluding a step with respect to an effect/outcome implicitly providessupport for the referenced step providing ≥˜1%, ≥˜5%, ≥˜10%, ≥˜20%,≥˜25%, ≥˜33%, ≥˜50%, ≥˜51%, ≥˜66%, ≥˜75%, ≥˜90%, ≥˜95%, ≥˜99%, or ˜100%of the effect/outcome, representing ≥˜1%, ≥˜5%, ≥˜10%, ≥˜20%, ≥˜25%,≥˜33%, ≥˜50%, ≥˜51%, ≥˜66%, ≥˜75%, ≥˜90%, ≥˜95%, ≥˜99%, or ˜100% of thesteps/effort performed, or both. Explicit listing of percentages ofelements/steps in connection with aspects does not limit or contradictsuch implicit disclosure.

Uncontradicted, terms such as “comprising” when used in connection witha step of a method provide implicit support for performing the steponce, ≥2 times, or until an associated function/effect is achieved.

Uncontradicted, the term “one” means a single type, singleiteration/copy/thing, of a recited element or step, or both, which willbe clear from context. For example, the referent “one” used with acomponent of a composition can refer to one type of element (which maybe present in numerous copies, as in the case of an ingredient in acomposition), one unit of the element, or both. Similarly, “one”component, a “single” component, or the “only component” of a systemtypically means 1 type of element (which may be present in numerouscopies), 1 instance/unit of the element, or both. Further, “one” step ofa method typically means performing one type of action (step), oneiteration of a step, or both. Uncontradicted, a disclosure of “one”element provides support for both, but uncontradicted, any claim to any“one” element means one type of such an element (e.g., a component of acomposition/system).

Uncontradicted, the term “some” means ≥2 copies/instances or ≥5% of alisted collection/whole is, or is made up of, an element. Regardingmethods, some means ≥5% of an effect, effort, or both, is made up of oris attributable to a step (e.g., as in “some of the method is performedby step Y”) or indicates a step is performed ≥2 times (e.g., as in “stepX is repeated some number of times”). “Predominately,” “most,” “mostly,”or “primarily,” means detectably >50% (e.g., mostly comprises,predominately includes, etc., mean >50%) (e.g., a system that mostlyincludes element X is composed of >50% of element X). The term“generally” means ≥75% (e.g., generally consists of, generallyassociated with, generally comprises, etc., means ≥75%) (e.g., a methodthat generally consists of step X means that 75% of the effort or effectof the method is attributable to step X). “Substantially” or “nearly”means ≥95% (e.g., nearly all, substantially consists of, etc., mean≥95%) (e.g., a collection that nearly entirely is made up of element Xmeans that at least 95% of the elements in the collection are elementX).

Uncontradicted, any aspect described with respect to an optionallypresent element(s)/step(s) also provides implicit support forcorresponding aspect(s) in which one, some, most, generally all, nearlyall, essentially all, or all such element(s) are lacking/step(s) notperformed, in respect of the relevant aspect. E.g., disclosure of asystem comprising element X implicitly also supports a system lackingelement X.

Uncontradicted, changes to tense or presentation of terms (e.g., using“comprises predominately” in place of “predominately comprises”) do notchange the meaning of the corresponding term/phrase.

Uncontradicted, all methods described here can be performed in anysuitable order regardless of presentation (e.g., a method comprisingsteps A, B, and C, can be performed in the order C, B, and A; B and Aand C simultaneously, etc.). Uncontradicted, elements of a collection,system, device, or composition can be assembled in any suitable mannerby any suitable method. In general, any methods and materials similar orequivalent to those described here can be used in the practice ofembodiments. Uncontradicted, the use of ordinal numbers such as “first,”“second,” “third,” and so on, is intended to distinguish respectiveelements rather than to denote a particular order of those elements.

Uncontradicted, any elements, steps, components, or features of aspectsand all variations thereof, etc., are within the scope of the invention.

Elements associated with a function can be described as “means for”performing a function in a composition/device/system or a “step for”performing a part of a method, and parts of this disclosure refer to“equivalents,” which means equivalents known in the art for achieving areferenced function associated with disclosed mean(s)/step(s). However,no element of this disclosure or claim should be interpreted as limitedto a “means-plus-function” construction unless such intent is clearlyindicated using the terms “means for” or “step for.” Terms such as“configured to” or “adapted to” do not indicate “means-plus-function”interpretation, but, rather, describe element(s)/step(s) configured to,designed to, selected to, or adapted to achieve a certain performance,characteristic, property, or the like using teachings provided here orin the art.

All references (e.g., publications, patent applications, and patents)cited herein are hereby incorporated by reference as if each referencewere individually and specifically indicated to be incorporated byreference and set forth in its entirety herein. Uncontradicted, anysuitable principles, methods, or elements of such references(collectively “teachings”) can be combined with or adapted to aspects.However, citation/incorporation of patent documents is limited to thetechnical disclosure thereof and does not reflect any view regarding thevalidity, patentability, etc., thereof. In the event of any conflictbetween this disclosure and the teachings of such documents, the contentof this disclosure controls regarding aspects of the invention. Numerousreferences are cited here to concisely incorporate known information andaid skilled persons in putting aspects into practice. While efforts havebeen made to include the most relevant references for such purposes,readers will understand that not every aspect of every cited referencewill apply to every aspect of the invention.

Additional Terms, Concepts, and Acronyms

The following description of certain terms is provided to assist readersin understanding the invention. Additional defined terms may be onlyprovided in other parts of this disclosure and use of acronyms that arewell known in the art may not be provided here.

Uncontradicted, any description of the weight of any component withoutfurther description means a weight/volume percent (“w/v. %”). Ingeneral, measurements of components in liquid formulations here are inweight/volume percent.

Except where explicitly indicated or clearly indicated by context,“improved” herein means “increased.” In aspects, “improved” means“reduced,” such as with respect to the toxicity of a composition,adverse events, and other negative characteristics, properties, orevents. Uncontradicted, terms such as “enhanced,” “improved,” and thelike are used synonymously. Any description of an improvement, increase,reduction, or enhancement or use of similar language, means a detectableor significant (DOS) such improvement, increase, reduction, orenhancement (or the like).

Uncontradicted, as suggested above, the term “suitable” generally meansappropriate, acceptable, or in contexts sufficient, or providing atleast generally or substantially all of an intended function, withoutcausing or imparting significant negative/detrimental impact. Forexample, a suitable mixture means a mixture of elements/ingredientswhich may be present with one another without significant negativeimpact to any one or more such elements/ingredients in the mixture,e.g., the elements/ingredients are compatible with one another. Asanother example, suitable functionality means exhibiting/retainingfunction(s) that are not significantly different from a referencedcounterpart function.

Terms such as “ophthalmologically suitable” should be interpreted asreferencing a compound that is safe for ophthalmic delivery, orcompounds modified in such a way so as to make such compounds safe forophthalmic administration.

Described here are compositions which can be characterized, in aspects,by the elements of which they are comprised. In aspects, compositionsprovided by the invention are characterized as having one or more“components”. Used here, uncontradicted, the term “components” refers toone or compounds which provide a specific function. For example, a“quinolone antibiotic component” is a component of a compositioncomprising one or more constituents which each alone or togetherprovide(s) detectable or significant antimicrobial effect(s); an“anti-inflammatory steroid component” is a component of a compositioncomprising one or more constituents which each alone or togetherprovide(s) an anti-inflammatory effect, etc. Here, the term“constituents” typically refers to a compound of a component orcomposition. The term “agent” also can be used synonymously with“constituent”, “ingredient”, or “compound”. The term “ingredient”,“ingredients”, or “ingredient(s)” can refer to an individual compound(which may, or may not, be a constituent of a component) or a componentof a composition. Terms such as “product” are used here in reference tocompositions disclosed here. Based on context, such terms can eitherrefer to either formulation compositions disclosed here or othercompositions comprising such formulation compositions, such asdrug/device combinations, kits, and the like

A “therapeutically effective amount” typically means an amount of acompound or pharmaceutical composition that will elicit an intended(typically significant) biological or medical response of a tissue,system, animal, or human that is being sought by the researcher, medicaldoctor, or other clinician. In aspects, a therapeutically effectiveamount is demonstrated by at least one or at least two well controlledand adequate clinical studies in human subjects/patients (e.g., as wouldbe considered sufficient for pharmaceutical approval).

The term “effective”, when used in reference to an excipient/componentof a composition, refers to detectably or significantlyperforming/increasing the functionality of one or more actives orprimary ingredients of the composition or detectably or significantlymodifying one or more characteristics of the composition in one or moreintended manners (e.g., in terms of suspending the API for an excipientcharacterized as a suspending agent, in terms of buffering thecomposition for a component described as a buffer, etc.). An “effective”excipient is also an excipient that is suitable for ophthalmological usein terms of safety and maintaining effectiveness of associated API(s).For example, an effective amount of a suspension component is an amountthat at least detectably or significantly increases the particlesuspension of one or more active pharmaceutical ingredients (e.g., oneor more fluoroquinolone antibiotic compounds, one or more steroidanti-inflammatory compounds, one or more non-steroid anti-inflammatorycompounds, or any combination thereof), such that most, generally all,substantially all, or all particles of the composition are mostly,generally, or completely suspended for at least about75%, >˜80%, >˜85%, >˜90%, >95%, or, e.g., about 100% of the time theproduct is being applied or administered or, e.g., such that theuniformity of the composition does not change over a period of at leastabout 5 minutes, such as, e.g., >˜10 minutes, >˜20 minutes, >˜30minutes, >˜40 minutes, >˜50 minutes, >˜1 hour, >˜3 hours, >˜6hours, >˜12 hours, >˜18 hours, >˜24 hours, >˜2 days, >˜3 days, >˜4days, >˜5 days, >˜6 days, >˜1 week, >˜2 weeks, >˜3 weeks, >˜1 month, >˜2months, >˜3 months, >˜4 months, >˜5 months, >˜6 months, >˜1 year, >˜1.5years, >˜2 years, >˜2.5 years, or, e.g., >˜3 years or more.

Terms such as “ophthalmologically suitable” generally mean that areferenced composition, excipient, API, etc., is suitable forapplication to the eye, the area around the eye, or both (e.g., asdetermined by safety testing such as through one or more well-controlledclinical studies in relevant subjects resulting in a significantdetermination of suitability in terms of safety, toxicity, irritability,lack of other major adverse events associated with ophthalmologicalproducts, and the like). In certain embodiments, an ophthalmologicallysuitable composition is a composition which does not detectably orsignificantly irritate or inflame the eye or the area surrounding theeye (e.g., in a significant number of patients as determined throughsuch above-referenced studies), cause significant eye irritation, orcause the receiving subject to experience significant discomfort due toits application (again, typically as determined on a detectable orsignificant level through one or more well-controlled studies).Compositions, formulations, components/excipients, etc.,described/referenced with respect to compositions or methods of theinvention are implicitly to be understood as referring toophthalmologically suitable material(s)/composition(s).

Sometimes terms such as “pharmaceutically acceptable” or“pharmacologically acceptable” also are used here with respect tocompositions, excipients, steps, etc. In general, such terms should beconstrued the same as “ophthalmologically suitable.”

A suitable excipient/component typically means a pharmaceuticallyinactive component that is compatible with other ingredients of theformulation (does not cause such other components to be inactivated orunstable, react to form undesirable reactants, etc.), which is notdetectably or significantly deleterious to the recipient of thecomposition, which is formulated in combination with the APIs of thecomposition, and which typically detectably or significantly imparts oneor more characteristics to a composition/API, improves one or morecharacteristics of the composition/API (e.g., delivery, stability, form,distribution of APIs, chemical characteristics of the composition,etc.), or both. This concept of suitable “compatibility” is applicableto any combination of ingredients in a composition of the invention.

Many characteristics of compositions are provided here which aredescribed relative to storage conditions. In aspects, compositions areadministered by injection and products relate to injectable products. Inaspects, products disclosed herein are adapted to be administered or areadministered topically (e.g., as ophthalmic drops). In aspects, storageconditions relative to descriptions of product stability are differentfor injectable products vs. topically applied ophthalmic products.Stability can be assessed under any suitable temperature and humidityconditions, such as those applied for the relevant type of product byFDA. In aspects, particular temperature and humidity conditions areprovided. E.g., for topically applied ophthalmic products (e.g., drops)such conditions can be about 25° C. and about 40% relative humidity, orabout 40° C. and no more than about 25% relative humidity and forinjectable products such conditions can be 25° C. and about 60% relativehumidity or at about 40° C. and about 75% relative humidity.

SUMMARY OF THE INVENTION

The compositions and methods disclosed herein have many attributes andaspects including, but not limited to, those set forth in, e.g.,described or referenced in, this Summary of the Invention (“Summary”).This Summary is not intended to be all-inclusive, and the scope of theinvention is not limited to or limited by the aspects, features,elements, or embodiments provided in this Summary. The Summary isprovided for efficient illustrative purposes only and not restriction.Any aspects of compositions or methods described in this section can becombined with any other aspect in this section or any other part of thisdisclosure.

In aspects, the invention provides pharmaceuticallyacceptable/ophthalmologically suitable compositions or uses thereofcomprising a quinolone (e.g., fluroquinolone) antibiotic(s), one or moreanti-inflammatory steroid agents, or both. Such formulations can, inaspects, be characterized by being physically and chemically stablesuspensions or solutions, in cases with improvements in terms of lessflocculation, coagulation, and the like, with respect to otherformulations. In aspects, compositions provided by the invention provideboth broad-spectrum antibiotic activity and anti-inflammatory activityfrom one or more steroidal or non-steroidal agents.

In specific embodiments, the invention provides physically andchemically stable, pharmaceutically acceptable, and ophthalmologicallysuitable compositions comprising therapeutically effective amounts ofone or more moxifloxacin compounds and one or more loteprednol compoundsin a suspension.

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) a suspension component consisting of both (1) aneffective amount of least one non-ionic suspension agent and (2) aneffective amount of at least one ionic suspension agent; (b) at leasttwo pharmaceutical ingredients comprising (1) moxifloxacin in a range ofabout 0.01% to about 0.5% by weight, and (2) loteprednol in a range ofabout 0.1% to about 5% by weight, or a pharmaceutically acceptable saltsthereof; and (c) a pharmaceutically acceptable chelating agent thatresults in a significantly similar or improved stability of the activeingredients as compared to disodium edetate in a concentration of about0.1 to 0.5 mg/mL.

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) an effective amount of at least one ionic suspensionagent; (b) an effective amount of at least one non-ionic surfactant; (c)at least two pharmaceutical ingredients comprising (1) moxifloxacin in arange of about 0.01% to about 0.5% by weight, and (2) loteprednol in arange of about 0.1% to about 5% by weight, or a pharmaceuticallyacceptable salts thereof; and (d) a pharmaceutically acceptablechelating agent that results in a significantly similar or improvedstability of the active ingredients as compared to disodium edetate in aconcentration of about 0.1 to 0.5 mg/mL.

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) at least 1.5 wt. % of a suspension agent componentcomprising an effective amount of a natural or semi-synthetic suspensionagent other than xanthan gum; (b) at least two pharmaceuticalingredients comprising (1) moxifloxacin in a range of about 0.01% toabout 0.5% by weight, and (2) loteprednol in a range of about 0.1% toabout 5% by weight, or pharmaceutically acceptable salts thereof; and(c) a pharmaceutically acceptable chelating agent that results in asignificantly similar or improved stability of the active ingredients ascompared to disodium edetate in a concentration of about 0.1 to 0.5mg/mL, (d) wherein (a) the composition has a viscosity of about3.5-about 25 mPas and (b) the composition exhibits significantly lessflocculation, coagulation, clumping, or combination of any or allthereof as opposed to a corresponding formulation comprising xanthan gumin place of the suspension agent.

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) an effective amount of least one natural orsemi-synthetic suspension agent composed of a compound having an averagemolecular weight of between 10,000 and 1,000,000 Daltons; (b) at leasttwo pharmaceutical ingredients comprising (1) moxifloxacin in a range ofabout 0.01% to about 0.5% by weight, and (2) loteprednol in a range ofabout 0.1% to about 5% by weight, or a pharmaceutically acceptable saltsthereof; and (c) a pharmaceutically acceptable chelating agent thatresults in a significantly similar or improved stability of the activeingredients as compared to disodium edetate in a concentration of about0.1 to 0.5 mg/mL.

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) an effective amount of a suspension agent comprisingeffective amounts of two nonionic suspension agents, one of whichnonionic suspension agents having surface active activity; (b) at leasttwo pharmaceutical ingredients comprising (1) moxifloxacin in a range ofabout 0.01% to about 0.5% by weight, and (2) loteprednol in a range ofabout 0.1% to about 5% by weight, or pharmaceutically acceptable saltsthereof; and (c) a pharmaceutically acceptable chelating agent thatresults in a significantly similar or improved stability of the activeingredients as compared to disodium edetate in a concentration of about0.1 to 0.5 mg/mL.

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) an effective amount of a suspension agent; (b) aneffective amount of a polyoxyl-ethylated castor oil; (c) at least twopharmaceutical ingredients comprising (1) moxifloxacin in a range ofabout 0.01% to about 0.5% by weight, and (2) loteprednol in a range ofabout 0.1% to about 5% by weight, or pharmaceutically acceptable saltsthereof; and (d) a pharmaceutically acceptable chelating agent thatresults in a significantly similar or improved stability of the activeingredients as compared to disodium edetate in a concentration of about0.1 to 0.5 mg/mL.

In aspects, the invention provides a kit comprising a pharmaceuticallyacceptable composition as described above packaged in one or more singleuse containers, wherein the kit further comprises one or more deliverydevices for administering the composition to a recipient

In aspects, the invention provides a method of using any one or morepharmaceutically acceptable and ophthalmologically suitable compositionsdescribed herein to treat or prevent inflammation associated withphysical trauma to ophthalmic tissue(s), inflammation associated withmicrobial (e.g., bacterial) infection(s), inflammation resulting fromsurgical procedure(s), or any combination thereof.

In aspects, the invention provides a method of using any one or morepharmaceutically acceptable and ophthalmologically suitable compositionsdescribed herein to treat or prevent an ocular microbial infection.

In aspects, the invention provides a method of using any one or morepharmaceutically acceptable and ophthalmologically suitable compositionsdescribed herein to treat or prevent significant inflammation associatedwith physical trauma to ophthalmic tissue(s), significant inflammationassociated with microbial (e.g., bacterial) infection(s), inflammationresulting from surgical procedure(s), to treat or prevent an ocularmicrobial infection, or any combination thereof.

In aspects, the invention provides a method of treating or preventing adisease or condition benefiting from a combination therapy of aquinolone antibiotic antimicrobial component and a steroid or steroidand non-steroid anti-inflammatory component, the method comprisingadministering an effective amount of a pharmaceutically acceptable andophthalmologically suitable composition, comprising pharmaceuticallyacceptable amounts of any one or more compositions described above.

DETAILED DESCRIPTION OF THE INVENTION

For convenience, both combinations of elements/steps and individualelements/steps may be described in this section of this disclosure.Despite the inclusion of passages focused on specific elements/steps,readers should understand that any aspect, facet, embodiment, or otherdescription of particular step(s) or element(s) can be applied to anygeneral description of the compositions/methods of the invention, or anyother recited element(s)/step(s) thereof, which are provided in any partof this disclosure.

Compositions

The invention provides compositions comprising a therapeuticallyeffective amount of pharmacologically acceptable/ophthalmologicallysuitable quinolone API(s), a therapeutically effective amount of apharmacologically acceptable/ophthalmologically suitable, ananti-inflammatory steroid API, or both, and an ophthalmologicallysuitable suspension component. Uncontradicted, “compositions” hereinmean compositions of the invention. As noted, compositions formed bymixtures of API(s) and excipients can be called formulations andformulation compositions are often simply called compositions, as willbe clear to readers from context. In other cases, compositions can referto drug/device combinations, kits, and other more complex compositions.The term composition also is sometimes used in reference toingredients/components, which will be clear from context.

In aspects, compositions/formulations comprise one or more additionalpharmacologically acceptable/ophthalmologically suitable excipients andAPI(s), typically ≥2 API(s) in combination. In cases, ≥2 APIs of aformulation are APIs that will DOS flocculate, coagulate, clump, cake,precipitate, or react or degrade, in a formulation that is notformulated with a suspension component provided here. Compositionsdescribed herein are suitable for ophthalmic application to a mammalianeye (e.g., to a human eye). In aspects, compositions comprise both atherapeutically effective amount of a quinolone antibiotic and atherapeutically effective amount of an anti-inflammatory steroidcomponent, in combination with an effective and suitable suspensioncomponent. In aspects, compositions described here are free of certainagents. E.g., in aspects compositions are free of one or more, or all,block copolymers of poly(ethylene oxide) and poly(propylene oxide)(e.g., Pluronic or Poloxamer excipients, such as those specificallydescribed in the Background of this disclosure), xanthan gum,crystalline cellulose/micro cellulose, or hydroxypropymethylcellulose(HPMC).

The quinolone antibiotic API(s) or steroid anti-inflammatory agentAPI(s) of the formulation and the suspension agent are sometimescollectively described as the “primary ingredients” offormulations/compositions. In aspects, the “primary ingredients” also oralternatively include a surfactant component, such as a non-ionicsurfactant component, a chelator component, or both. In aspects, anon-ionic surfactant of the composition also acts as a suspension agent.Additional ingredients, which in aspects are optional ingredients butwhich in embodiments can be required, are also described here. Suchingredients can, in aspects, provide one or more measurable, e.g.,detectable or significant effect(s) when provided in effective amounts.In aspects, additional ingredients can be provided to aid in compositionstability, composition application, composition characteristics (e.g.,pH), composition effect, or any combination thereof. In aspects, one ormore additional ingredients are directly related to a detectable orsignificant therapeutic/physiological effect, an effect on shelf life ofthe product, an effect on patient compliance, an effect in distributionof the product, etc. In aspects, one or more additional ingredients aredirectly related to a detectable or significant effect on productusability, such as, e.g., the prevention of the development of adetectable or significant non-uniform consistency of a composition,which in aspects is not directly related to a therapeutic effect yetcan, in aspects, be directly related to the suitability of thecomposition for use in the eye.

In aspects, compositions comprise at least one quinolone antibioticcomponent and at least one anti-inflammatory component, which can be anNSAD, an anti-inflammatory steroid, another anti-inflammatory agent, ora combination of any or all thereof. In aspects, compositions providedby the invention comprise at least 2, such as, e.g., ≥˜3, ≥˜4, or ≥˜5 ormore active pharmaceutical ingredients (APIs). In aspects, the inventionprovides compositions comprising between 2-3 APIs (e.g., ≥2 quinoloneantibiotic APIs and ≥1 anti-inflammatory steroid(s) or ≥1 quinoloneantibiotic API(s) and ≥2 anti-inflammatory steroid APIs). In aspects,compositions comprise at least one quinolone antibiotic, e.g., at leastone fluoroquinolone antibiotic. As noted, quinolone antibiotics can varyin terms of formulation properties, efficacy properties, and the like.Accordingly, certain aspects of the invention are limited to certaintypes of quinolone antibiotics. In aspects, compositions also oralternatively comprise at least one non-steroidal anti-inflammatorycompound. In aspects, compositions comprise at least one steroidalanti-inflammatory compound and at least one non-steroidalanti-inflammatory compound.

Ingredients

To better illuminate the scope of the invention, a description ofclasses of ingredients of compositions/formulations of the invention isprovided in this section.

Quinolone Antibiotic Component

In aspects, compositions comprise one or more quinolone antibioticcomponents. A quinolone antibiotic component means any ≥1 quinoloneantibiotics, such as those quinolone antibiotics specifically referredto herein, equivalents thereof known in the art, effectivederivatives/analogs thereof, or any suitable salt, hydrate, solvate,ether, ester, acetal, polymorph, and ketal thereof. In general, anyquinolone antibiotic(s) can be included in formulations. However,readers will understand that certain quinolone antibiotic(s) describedherein have advantageous properties and represent unique aspects of theinvention.

In aspects, ≥1 of the quinolone antibiotics has a structure based on the4-quinolone ring structure or having a structure according to Formula I—

Wherein R1, R5-R8, & X are optionally any pharmaceutically acceptablesubstituent. In aspects, R1 is a cyclopropane or a difluorobenzene; R5is an amino, hydroxyl, or methyl; R6 is a fluorine; R7 is an alkylsubstituent, such as a nitrogen containing cycloalkyl(heterocycloalkyl); and R8 is a fluorine-, chlorine-, nitrogen-, orcarbon-containing group, e.g., as exemplified in Pham et al., Med. Chem.Commun., 2019, 10, 1719-1739, DOI: 10.1039/C9MD00120D, which isspecifically incorporated herein by reference. In aspects, one or moreof positions (R) 6, 7, and 8 are substituted by fluoro,3-methylpiperazin-1-yl, and methoxy groups, respectively. The structureof quinolone/fluroquinolone antibiotics has been extensively studied inthe art and, accordingly, does not have to be further described herein.In aspects, X is a carbon, which is typically found in quinolones.

Some quinolone antibiotics demonstrate broad-spectrum activity. Somequinolone antibiotics do not demonstrate broad-spectrum activity. Inaspects, an effective amount of ≥1 quinolone antibiotics demonstratingbroad spectrum activity are present in compositions. In aspects, as aquinolone antibiotic, can be any pharmaceutically acceptable orophthalmologically suitable quinolone antibiotic, such as, e.g., firstgeneration quinolones (e.g., nalidixic acid and cinoxacin), secondgeneration quinolones (e.g., norfloxacin, lomefloxacin, enoxacin,ofloxacin, and ciprofloxacin), third generation quinolones (e.g.,levofloxacin, sparfloxacin, gatifloxacin, and moxifloxacin), or fourthgeneration quinolones (e.g., trovafloxacin and gemifloxacin). Theclassification of the “generation” of quinolone antibiotics varies inthe art, but in general these classes are now fairly well defined in theart based on functionality of included antibiotics (e.g., thirdgeneration fluroquinolones exhibit broad spectrum activity againstaerobic gram-negative and gram-positive bacteria and fourth generationfluroquinolones, e.g., exhibit both broad-spectrum activity againstaerobic and anaerobic species. See, e.g., Scoper S V. Review of third-and fourth-generation fluoroquinolones in ophthalmology: in-vitro andin-vivo efficacy. Adv Ther. 2008 October; 25(10):979-94. doi:10.1007/s12325-008-0107-x. PMID: 18836691; Mather R, Karenchak L M,Romanowski E G, Kowalski R P. Fourth generation fluoroquinolones: newweapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002April; 133(4):463-6. doi: 10.1016/s0002-9394(02)01334-x. PMID: 11931779;and King et al., Am Fam Physician. 2000 May 1; 61(9):2741-2748.

In aspects, the quinolone antibiotic component comprises ≥1 quinoloneantibiotic APIs which are any ophthalmologically suitable andclassified/classifiable as broad-spectrum antibiotic compound(s). Inaspects, the quinolone antibiotic is any ophthalmologically suitablequinolone antibiotic demonstrating suitable therapeutic efficacy againsta target infective agent (such as, e.g., common ocular infective agentssuch as Staphylococcal & Haemophilus species).

In aspects, quinolone antibiotic components comprise one or moreophthalmologically suitable antibiotic compounds classifiable as afluoroquinolone, chloroquine, or hydroxychloroquine. In aspects, aquinolone compound is a fluoroquinolone antibiotic compound. In aspects,compositions can comprise any suitable ≥1 fluoroquinolone compound(s).Exemplary fluoroquinolone compounds include, e.g., ciprofloxacin,ofloxacin, gemifloxacin, levofloxacin, moxifloxacin, and gatifloxacin.In aspects, fluoroquinolone antibiotic(s) in compositions includemoxifloxacin, ofloxacin, ciprofloxacin, fleroxacin, lomefloxacin,nadifloxacin, norfloxacin, pefloxacin, rufloxacin, balofloxacin,grepafloxacin, levofloxacin, pazufloxacin, sparfloxacin, temafloxacin,clinafloxacin, gatifloxacin, sitafloxacin, prulifloxacin, besifloxacin,delafloxacin, etc. In aspects, one or more derivatives of suchcompositions are included. Examples of known derivatives include, e.g.,delafloxacin, finafloxacin, ozenoxacin, avarofloxacin, cadazolid,zabofloxacin, lascufloxacin, nemonoxacin, ophthalmologically suitable(e.g., modified for ophthalmological use) OPS-2017 levonadifloxacin (WCK771)+alalevonadifloxacin (WCK 23491, oral prodrug), TNP-2092 (arifamycin-quinolizinone hybrid), MCB3837 (oxazolidinone-quinolonehybrid). In aspects, a derivative is a structurally similar compoundhaving suitable, similar, or improved properties with respect to one ormore known “parent” APIs, such as moxifloxacin or gatifloxacin. Inaspects, compositions can comprise one or more therapeutically effectiveand ophthalmologically suitable derivative of any one or more quinolonecompounds described herein, such as any therapeutically effective andophthalmologically suitable derivative of a core quinolone structure(e.g., according to Formula 1, supra), wherein modifications are madeat, e.g., one or more of R1 or R5-R8 thereof.

In aspects, the quinolone antibiotic component of compositions providedby the invention comprise one or more therapeutically effective andophthalmologically suitable quinolone compounds, such as, e.g., afluoroquinolone compound, in an amount representing between about 0.01-1wt. % of the composition, such as, e.g., between ˜0.01-˜0.9 wt. %,˜0.01-˜0.8 wt. %, ˜0.01-˜0.7 wt. %, ˜0.01-˜0.6 wt. %, ˜0.01-˜0.5 wt. %,˜0.01-˜0.4 wt. %, ˜0.01-˜0.3 wt. %, ˜0.01-˜0.2 wt. %, ˜0.01-˜0.1 wt. %,such as, e.g., between ˜0.02-˜1 wt. %, ˜0.03-1 wt. %, ˜0.04-˜ wt. %,˜0.05-˜ wt. %, ˜0.06-1 wt. %, ˜0.07-˜wt. %, ˜0.08-˜ wt. %, ˜0.09-1 wt.%, ˜0.1-1 wt. %, as in, for example, between ˜0.02-˜0.8 wt. %,˜0.03-˜0.7 wt. %, ˜0.04-˜0.6 wt. %, ˜0.05-˜0.4 wt. %, ˜0.06-˜0.3 wt. %,˜0.07-˜0.2 wt. %, ˜0.08-˜0.2 wt. %, ˜0.09-˜0.2 wt. %, or, e.g., about0.1 wt. % of the composition. In aspects, the quinolone compound is afluoroquinolone.

In aspects, compositions comprise between about 0.01-10 mg/mL of atherapeutically effective and ophthalmologically suitable quinoloneantibiotic compound, such as, e.g., between ˜0.01-˜9 mg/mL, ˜0.01-˜8mg/mL, ˜0.01-˜7 mg/mL, ˜0.01-˜6 mg/mL, ˜0.01-˜4 mg/mL, ˜0.01-˜3 mg/mL,˜0.01-˜2 mg/mL, ˜0.01-˜1 mg/mL, such as, e.g., between ˜0.05-˜10 mg/mL,˜0.1-˜10 mg/mL, ˜0.15-˜10 mg/mL, ˜0.20-˜10 mg/mL, ˜0.25-˜10 mg/mL,˜0.30-˜10 mg/mL, ˜0.35-10 mg/mL, ˜0.40-10 mg/mL, ˜0.45-10 mg/mL,˜0.50-˜10 mg/mL, ˜0.55-˜10 mg/mL, ˜0.60-˜10 mg/mL, ˜0.65-˜10 mg/mL,˜0.70-˜mg/mL, ˜0.75-˜10 mg/mL, ˜0.80-˜10 mg/mL, ˜0.85-˜10 mg/mL,˜0.90-˜10 mg/mL, ˜0.95-10 mg/mL, 1-˜10 mg/mL, as in, for example,between ˜0.1-9 mg/mL, ˜0.2-˜8 mg/mL, ˜0.3-˜7 mg/mL, ˜0.4-˜ 6 mg/mL,˜0.5-˜5 mg/mL, ˜0.6-˜4 mg/mL, ˜0.7-˜3 mg/mL, ˜0.8-˜2 mg/L, ˜0.9-˜2mg/mL, ˜0.9-˜1.9 mg/mL, ˜0.9-˜1.8 mg/mL, ˜0.9-˜1.7 mg/mL, ˜0.9-˜1.6mg/mL, ˜0.9-˜1.5 mg/mL, ˜0.9-˜1.4 mg/mL, ˜0.9-˜1.3 mg/mL, ˜0.9-˜1.2mg/mL, or ˜0.9-˜1.1 mg/mL, or, e.g., about 1 mg/mL of a quinoloneantibiotic compound. In aspects, the quinolone compound is afluoroquinolone.

In aspects, compositions comprise between about 0.01-2 wt. % of atherapeutically effective and ophthalmologically suitable quinoloneantibiotic compound, such as, e.g., a fluoroquinolone compound, such as,e.g., between ˜0.01-˜1.9 wt. %, ˜0.01-1.8 wt. %, ˜0.01-˜1.7 wt. %,˜0.01-˜1.6 wt. %, ˜0.01-˜1.5 wt. %, ˜0.01-˜1.4 wt. %, ˜0.01-1.3 wt. %,˜0.01-˜1.2 wt. %, ˜0.01-˜1.1 wt. %, ˜0.01-˜1 wt. %, ˜0.01-˜0.9 wt. %,˜0.01-˜0.8 wt. %, ˜0.01-˜0.7 wt. %, ˜0.01-˜0.6 wt. %, ˜0.01-˜0.5 wt. %,˜0.01-˜0.4 wt. %, ˜0.01-˜0.3 wt. %, ˜0.01-˜0.2 wt. %, ˜0.01-˜0.1 wt. %such as, e.g., between ˜0.02-˜2 wt. %, ˜0.03˜2 wt. %, ˜0.04-˜2 wt. %,˜0.05-˜2 wt. %, ˜0.06-˜2 wt. %, ˜0.07-˜2 wt. %, ˜0.08-˜2 wt. %, ˜0.09-˜2wt. %, ˜1-2 wt. %, ˜1.1-˜2 wt. %, ˜1.2-˜2 wt. %, ˜1.3-˜2 wt. %, ˜1.4-˜2wt. %, ˜1.5-˜2 wt. %, ˜1.6-˜2 wt. %, ˜1.7-˜2 wt. %, ˜1.8-˜2 wt. %,˜1.9-˜2 wt. %, as in, for example, between ˜0.02-˜1.9 wt. %, ˜0.03-˜1.8wt. %, ˜0.04-˜1.7 wt. %, ˜0.05-˜1.6 wt. %, ˜0.06-˜1.5 wt. %, ˜0.07-˜1.4wt. %, ˜0.08-˜1.3 wt. %, ˜0.09-˜1.2 wt. %, ˜0.1-˜1.1 wt. %, ˜0.2-˜1 wt.%, ˜0.3-˜0.9 wt. %, ˜0.4-˜0.8 wt. %, ˜0.4-˜0.7 wt. %, ˜0.4-˜0.6 wt. %or, e.g., about 0.5 wt. %. of a quinolone antibiotic compound. Inaspects, the quinolone compound is a fluoroquinolone compound.

In aspects, compositions comprise between about 1-10 mg/mL of atherapeutically effective and ophthalmologically suitable quinoloneantibiotic compound, such as, e.g., a fluoroquinolone compound such as,e.g., between ˜1-˜9.5 mg/mL, ˜1-9 mg/mL, ˜1-˜8.5 mg/mL, ˜1-˜8 mg/mL,˜1-7.5 mg/mL, ˜1-˜7 mg/mL, 1-˜6.5 mg/mL, ˜1-˜6 mg/mL, 1-˜5.5 mg/mL,˜1-˜5 mg/mL, ˜1-˜4.5 mg/mL, ˜1-˜4 mg/mL, ˜1-˜3.5 mg/mL, ˜1-˜3 mg/mL,˜1-˜2.5 mg/mL, ˜1-˜2 mg/mL, ˜1-˜1.5 mg/mL, such as, e.g. ˜1.5-˜10 mg/mL,˜2-˜10 mg/mL, ˜2.5-˜10 mg/mL, ˜3-˜10 mg/mL, ˜3.5-˜10 mg/mL, ˜4-˜10mg/mL, ˜4.5-˜10 mg/mL, ˜5-˜10 mg/mL, ˜5.5-˜10 mg/mL, ˜6-˜10 mg/mL,˜6.5-˜10 mg/mL, ˜7-˜10 mg/mL, ˜7.5-˜10 mg/mL, ˜8-˜10 mg/mL, ˜8.5-˜10mg/mL, ˜9-˜10 mg/mL, ˜9.5-˜10 mg/mL as in, for example, between˜1.5-˜9.5 mg/mL, ˜2-˜9 mg/mL, ˜2.5-˜8.5 mg/mL, ˜3-˜8 mg/mL, ˜3.5-˜7.5mg/mL, ˜4-˜7 mg/mL, ˜4.5-6.5 mg/mL, ˜4.5-˜6 mg/mL, ˜4.5-˜5.5 mg/mL, or,e.g., about 5 mg/mL of a quinolone compound. In aspects, the quinolonecompound is a fluoroquinolone compound.

In aspects, compositions comprise a quinolone antibiotic componentcomprising one or more quinolone antibiotic compounds, such as, e.g.,one or more fluoroquinolone compounds, demonstrating a microbialinhibition activity of at least that demonstrated by moxifloxacin, atleast that demonstrated by gatifloxacin, or both, against commonophthalmic infective microbes, such as, e.g., Haemophilus influenza,Streptococcus pneumoniae, and Staphylococcus aureus, coagulase-negativestaphylococci, Pseudomonas aeruginosa, gram negative bacilli, etc.

Moxifloxacin

In certain aspects, compositions provided by the invention comprise,e.g., a quinolone antibiotic component of compositions provided by theinvention comprise, mostly comprise, generally consist of, substantiallyconsist of, or consist of one or more moxifloxacin compounds (anysuitable salt form of moxifloxacin, such as a hydrocholoride formthereof, any suitable derivative of moxifloxacin, or a combinationthereof). Moxifloxacin compounds inhibit the bacterial enzymes DNAgyrase (topoisomerase II) and topoisomerase IV, resulting in inhibitionof DNA replication and repair and cell death in sensitive bacterialspecies.

In aspects, the invention provides ophthalmic compositions comprisingone or more ophthalmologically suitable compounds which, when deliveredto the eye of a subject in sufficient amounts, result in detectable orsignificant antimicrobial effects, approximately the same orsignificantly similar to those typically provided by a correspondingamount of moxifloxacin hydrochloride or that provide an improvement onsuch effects. In aspects, such compositions comprise one or moremoxifloxacin compounds. In aspects, one or more of such moxifloxacincompounds also provide therapeutic effects significantly similar to, orthat improve upon, therapeutic effects associated with moxifloxacinhydrochloride in similar application and amount. In aspects,moxifloxacin compounds are mostly, generally, or only composed ofmoxifloxacin, rather than an analog or derivative thereof. In aspects,moxifloxacin compounds comprise, mostly comprise, or only comprise oneor more suitable moxifloxacin analogs or derivatives which can vary, forexample, by providing different phenol and alkyl halide(s) at the thirdposition of the carboxylic group via an esterification reaction (see,e.g., Akhtar, et. al., in “Moxifloxacin-Ester derivatives: Synthesis,characterization and pharmacological evaluation,” Pak J Pharm Sci. 2019May; 32 (3 Special):301-1306); modifications to the core of moxifloxacin(e.g., 8D derivative described by, e.g., Rocha-Roa, et. al. in “Insilico study of Moxifloxacin derivatives with possible antibacterialactivity against a resistant form of DNA gyrase from Porphyromonasgingivalis”, Archives of Oral Biology, Volume 95, November 2018, Pages30-39), and, e.g., introduction of alky, acyl, or sulfonyl moieties tothe basic secondary amine moiety of moxifloxacin (see, e.g., Kulabas,et. al. in “Design, synthesis and molecular modeling studies on novelmoxifloxacin derivatives as potential antibacterial and antituberculosisagents,” Bioorg Chem. 2019 July; 88:102965, Epub 2019 May 2), etc.

In aspects, compositions provided by the invention comprises any form ofophthalmologically suitable moxifloxacin compound, such as, e.g., anypharmaceutically acceptable derivative, prodrug, hydrate, salt, solvate,enantiomer, or polymorph thereof. In aspects, moxifloxacin compounds ofthe compositions provided by the invention comprise anyophthalmologically suitable analog or derivative of moxifloxacin. Inaspects, compositions provided by the invention comprise a single typeof moxifloxacin compound, while in alternative aspects, compositionscomprise two or more types of moxifloxacin compounds e.g., two differentderivatives of moxifloxacin, each differing from the other in, e.g.,their compound size, level of detectable effect (e.g., microbialinhibition activity), pKa value, etc.

In certain aspects, compositions provided by the invention comprise asalt of moxifloxacin. In aspects, most, generally all, or all of themoxifloxacin compound(s) comprise moxifloxacin in one or more saltforms. In aspects, the moxifloxacin comprises, mostly comprises,generally consists of, consists of, or consists essentially ofmoxifloxacin hydrochloride. In aspects, a quinolone antibiotic componentis composed of ≥2 APIs, of which a moxifloxacin component, such asmoxifloxacin HCl, is one component. Moxifloxacin hydrochloride is an8-methoxy fluoroquinolone anti-infective, with a diazabicyclononyl ringat the C7 position. Moxifloxacin hydrochloride is chemically1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolol[3,4b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid, monohydrochloride(molecular formula C21H24FN3O4.HCl).

Moxifloxacin Amount

According to aspects, the invention provides an ophthalmologicallysuitable composition comprising an effective amount of moxifloxacincompound(s), such as, e.g., a salt of moxifloxacin, such as, e.g.,moxifloxacin HCl, wherein the ophthalmologically suitable moxifloxacincompound is present in the composition in an amount representing betweenabout 0.01-1 wt. % of the composition, such as, e.g., between ˜0.01-˜0.9wt. %, ˜0.01-˜0.8 wt. %, ˜0.01-˜0.7 wt. %, ˜0.01-˜0.6 wt. %, ˜0.01-˜0.5wt. %, ˜0.01-˜0.4 wt. %, ˜0.01-˜0.3 wt. %, ˜0.01-˜0.2 wt. %, ˜0.01-˜0.1wt. %, such as, e.g., between ˜0.02-1 wt. %, ˜0.03-˜wt. %, ˜0.04-˜ wt.%, ˜0.05-1 wt. %, ˜0.06-1 wt. %, ˜0.07-˜ wt. %, ˜0.08-1 wt. %, ˜0.09-˜1wt. %, ˜0.1-˜1 wt. %, as in, for example, between ˜0.02-˜0.8 wt. %,˜0.03-˜0.7 wt. %, ˜0.04-˜0.6 wt. %, ˜0.05-˜0.4 wt. %, ˜0.06-˜0.3 wt. %,˜0.07-˜0.2 wt. %, ˜0.08-˜0.2 wt. %, ˜0.09-˜0.2 wt. %, or, e.g., about0.1 wt. % of the composition.

In aspects, the invention provides an ophthalmologically suitablecomposition comprises an effective amount of moxifloxacin compound(s),such as, e.g., a salt of moxifloxacin, such as, e.g., moxifloxacin HCl,wherein the composition comprises between about 0.01-about 10 mg/mL,such as, e.g., between ˜0.01-˜9 mg/mL, ˜0.01-˜8 mg/mL, ˜0.01-˜7 mg/mL,˜0.01-˜6 mg/mL, ˜0.01-˜4 mg/mL, ˜0.01-˜3 mg/mL, ˜0.01-˜2 mg/mL, ˜0.01-˜1mg/mL, such as, e.g., between ˜0.05-˜10 mg/mL, ˜0.1-˜10 mg/mL, ˜0.15-˜10mg/mL, ˜0.20-˜10 mg/mL, ˜0.25-˜10 mg/mL, ˜0.30-˜10 mg/mL, ˜0.35-˜10mg/mL, ˜0.40-˜10 mg/mL, ˜0.45-˜10 mg/mL, ˜0.50-˜10 mg/mL, ˜0.55-˜10mg/mL, ˜0.60-˜10 mg/mL, ˜0.65-˜10 mg/mL, ˜0.70-˜mg/mL, ˜0.75-˜10 mg/mL,˜0.80-˜10 mg/mL, ˜0.85-˜10 mg/mL, ˜0.90-˜10 mg/mL, ˜0.95-˜10 mg/mL,˜1-10 mg/mL, as in, for example, between ˜0.1-9 mg/mL, ˜0.2-˜8 mg/mL,˜0.3-˜7 mg/mL, ˜0.4-˜ 6 mg/mL, ˜0.5-˜5 mg/mL, ˜0.6-˜4 mg/mL, ˜0.7-˜3mg/mL, ˜0.8-˜2 mg/L, ˜0.9-˜2 mg/mL, ˜0.9-˜1.9 mg/mL, ˜0.9-˜1.8 mg/mL,˜0.9-˜1.7 mg/mL, ˜0.9-˜1.6 mg/mL, ˜0.9-˜1.5 mg/mL, ˜0.9-˜1.4 mg/mL,˜0.9-˜1.3 mg/mL, ˜0.9-˜1.2 mg/mL, or ˜0.9-1.1 mg/mL, or, e.g., about 1mg/mL of a moxifloxacin compound such as moxifloxacin hydrochloride.

In general, an “effective amount” of an API of a composition, or acomposition overall, as exemplified/discussed elsewhere, is an amountthat is suitable for causing a significant therapeutic effect in asubject, such as a human patient. As discussed below, “efficacy” and“effectiveness” in terms of excipients and other ingredients isdetermined by a measurable or significant effect of thecomponent/excipient for such a component's/ingredient's intendedpurpose.

According to certain aspects, compositions comprise moxifloxacin plusone or more additional antimicrobial compounds, such as, e.g., one ormore quinolone antibiotics, or specifically one or more fluoroquinoloneantibiotics, including, e.g., one or more of ofloxacin, ciprofloxacin,fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, pefloxacin,rufloxacin, balofloxacin, grepafloxacin, levofloxacin, pazufloxacin,sparfloxacin, temafloxacin, clinafloxacin, gatifloxacin, sitafloxacin,prulifloxacin, besifloxacin, gemifloxacin, and delafloxacin.

Gatifloxacin

In certain aspects, compositions provided by the invention comprise,e.g., a quinolone antibiotic component of compositions provided by theinvention comprise, a gatifloxacin compound. Gatifloxacin compounds canexhibit inhibition of DNA gyrase, an enzyme involved in DNA replication,transcription and repair, and inhibition of topoisomerase IV, an enzymeinvolved in partitioning of chromosomal DNA during bacterial celldivision.

In aspects, the invention provides ophthalmic compositions comprisingone or more ophthalmologically suitable compounds which, when deliveredto the eye of a subject in sufficient amounts, result in detectable orsignificant antimicrobial properties (that is, provide detectable orsignificant inhibition of growth of one or more microbes) approximatelythe same or significantly similar to those typically provided by acorresponding amount of gatifloxacin or that provide an improvement onsuch effects. In aspects, such compositions comprise one or moregatifloxacin compounds. In aspects, one or more of such gatifloxacincompounds also provide therapeutic effects significantly similar to, orthat improve upon, therapeutic effects associated with gatifloxacin insimilar application and amount. In aspects, gatifloxacin compounds aremostly, generally, or only composed of gatifloxacin, rather than ananalog or derivative thereof. In aspects, gatifloxacin compoundscomprise, mostly comprise, or only comprise one or more suitablegatifloxacin analogs or derivatives such as, e.g., those described bySriram, et. al., in “Gatifloxacin derivatives: synthesis,antimycobacterial activities, and inhibition of Mycobacteriumtuberculosis DNA gyrase,” Bioorg Med Chem Lett. 2006 Jun. 1;16(11):2982-5; by Gomez, et. al., in “Synthesis of gatifloxacinderivatives and their biological activities against Mycobacterium lepraeand Mycobacterium tuberculosis,” Bioorg Med Chem. 2013 Feb. 15;21(4):948-56; and, e.g., by de Almeida M V, et. al., in “Synthesis andantitubercular activity of lipophilic moxifloxacin and gatifloxacinderivatives,” Bioorg Med Chem letters, 17, 5661-5664(2007).

In aspects, compositions provided by the invention comprise any form ofophthalmologically suitable gatifloxacin compound, such as, e.g., anypharmaceutically acceptable derivative, prodrug, hydrate, salt, solvate,enantiomer, or polymorph thereof. In aspects, gatifloxacin compounds ofthe compositions provided by the invention comprise anyophthalmologically suitable analog or derivative of gatifloxacin. Inaspects, compositions provided by the invention comprise a single typeof gatifloxacin compound, while in alternative aspects, compositionsprovided by the invention comprise ≥2 types of gatifloxacin compoundse.g., two different derivatives of gatifloxacin, each differing from theother in, e.g., their compound size, level of detectable effect (e.g.,microbial inhibition activity), pKa value, etc.

In certain aspects, compositions provided by the invention comprise asalt of gatifloxacin. In aspects, most, generally all, or all of thegatifloxacin compound(s) comprise gatifloxacin((+)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylicacid sesquihydrate), in one or more salt forms.

Gatifloxacin Amount

According to aspects, the invention provides an ophthalmologicallysuitable composition comprising an effective amount of gatifloxacincompound(s), such as, e.g., gatifloxacin, wherein the ophthalmologicallysuitable gatifloxacin compound is present in the composition in anamount of between about 0.01-2 wt. % such as, e.g., between ˜0.01-˜1.9wt. %, ˜0.01-1.8 wt. %, ˜0.01-˜1.7 wt. %, ˜0.01-˜1.6 wt. %, ˜0.01-˜1.5wt. %, ˜0.01-˜1.4 wt. %, ˜0.01-˜1.3 wt. %, ˜0.01-˜1.2 wt. %, ˜0.01-˜1.1wt. %, ˜0.01-˜1 wt. %, ˜0.01-˜0.9 wt. %, ˜0.01-˜0.8 wt. %, ˜0.01-˜0.7wt. %, ˜0.01-˜0.6 wt. %, ˜0.01-˜0.5 wt. %, ˜0.01-˜0.4 wt. %, ˜0.01-˜0.3wt. %, ˜0.01-˜0.2 wt. %, ˜0.01-˜0.1 wt. % such as, e.g., between˜0.02-˜2 wt. %, ˜0.03 ˜2 wt. %, ˜0.04-˜2 wt. %, ˜0.05-˜2 wt. %, ˜0.06-˜2wt. %, ˜0.07-˜2 wt. %, ˜0.08-˜2 wt. %, ˜0.09-˜2 wt. %, ˜1-2 wt. %,˜1.1-˜2 wt. %, ˜1.2-˜2 wt. %, ˜1.3-˜2 wt. %, ˜1.4-˜2 wt. %, ˜1.5-˜2 wt.%, ˜1.6-˜2 wt. %, ˜1.7-˜2 wt. %, ˜1.8-˜2 wt. %, ˜1.9-˜2 wt. %, as in,for example, between ˜0.02-˜1.9 wt. %, ˜0.03-˜1.8 wt. %, ˜0.04-˜1.7 wt.%, ˜0.05-˜1.6 wt. %, ˜0.06-˜1.5 wt. %, ˜0.07-˜1.4 wt. %, ˜0.08-˜1.3 wt.%, ˜0.09-1.2 wt. %, ˜0.1-˜1.1 wt. %, ˜0.2-1 wt. %, ˜0.3-˜0.9 wt. %,˜0.4-˜0.8 wt. %, ˜0.4-˜0.7 wt. %, ˜0.4-˜0.6 wt. % or, e.g., about 0.5wt. %.

In aspects, compositions comprise between about 1-10 mg/mL of agatifloxacin compound, such as, e.g., between ˜1-˜9.5 mg/mL, ˜1-9 mg/mL,˜1-˜8.5 mg/mL, ˜1-˜8 mg/mL, 1-˜7.5 mg/mL, ˜1-˜7 mg/mL, ˜1-6.5 mg/mL,˜1-˜6 mg/mL, 1-˜5.5 mg/mL, ˜1-˜5 mg/mL, ˜1-˜4.5 mg/mL, ˜1-˜4 mg/mL,˜1-˜3.5 mg/mL, ˜1-˜3 mg/mL, ˜1-˜2.5 mg/mL, ˜1-˜2 mg/mL, ˜1-˜1.5 mg/mL,such as, e.g. ˜1.5-˜10 mg/mL, ˜2-˜10 mg/mL, ˜2.5-˜10 mg/mL, ˜3-˜10mg/mL, ˜3.5-˜10 mg/mL, ˜4-˜10 mg/mL, ˜4.5-˜10 mg/mL, ˜5-˜10 mg/mL,˜5.5-˜10 mg/mL, ˜6-˜10 mg/mL, ˜6.5-˜10 mg/mL, ˜7-˜10 mg/mL, ˜7.5-˜10mg/mL, ˜8-˜10 mg/mL, ˜8.5-˜10 mg/mL, ˜9-˜10 mg/mL, ˜9.5-˜10 mg/mL as in,for example, between ˜1.5-˜9.5 mg/mL, ˜2-˜9 mg/mL, ˜2.5-˜8.5 mg/mL,˜3-˜8 mg/mL, ˜3.5-˜7.5 mg/mL, ˜4-˜7 mg/mL, ˜4.5-6.5 mg/mL, ˜4.5-˜6mg/mL, ˜4.5-˜5.5 mg/mL, or, e.g., about 5 mg/mL of a gatifloxacincompound.

In general, an “effective amount” of an API of a composition, or acomposition overall, as exemplified/discussed elsewhere, is an amountthat is suitable for causing a significant therapeutic effect in asubject, such as a human patient. As discussed below, “efficacy” and“effectiveness” in terms of excipients and other ingredients isdetermined by a measurable or significant effect of thecomponent/excipient for such a component's/ingredient's intendedpurpose.

According to certain aspects, compositions comprise gatifloxacincompound(s) plus one or more additional antimicrobial compounds, suchas, e.g., one or more quinolone antibiotics, or specifically one or morefluoroquinolone antibiotics, including, e.g., one or more ofmoxifloxacin, ofloxacin, ciprofloxacin, fleroxacin, lomefloxacin,nadifloxacin, norfloxacin, pefloxacin, rufloxacin, balofloxacin,grepafloxacin, levofloxacin, pazufloxacin, sparfloxacin, temafloxacin,clinafloxacin, sitafloxacin, prulifloxacin, besifloxacin, gemifloxacin,and delafloxacin.

Anti-Inflammatory Component

In aspects, compositions provided by the invention comprise one or moreanti-inflammatory steroid components. In aspects, an anti-inflammatorysteroid component comprises a therapeutically effective amount of one ormore anti-inflammatory compounds. In aspects the anti-inflammatorycompounds are any one or more ophthalmologically suitableanti-inflammatory compounds, such as an anti-inflammatory classified asa steroid, such as, in specific aspects a corticosteroid, or anon-steroid (NSAID). In aspects, an anti-inflammatory compound is anyophthalmologically suitable form of such compounds, such as, e.g., anophthalmologically suitable salt, hydrate, solvate, ether, ester,acetal, prodrug, polymorph, and ketal thereof. Here, the termanti-inflammatory typically means a compound which DOS counteracts,e.g., suppresses or prevents, inflammation, but, as with all knownterms, such a description is only meant to illustrate aspects and not tolimit the scope of the term.

Steroids Including Corticosteroids & Glucocorticoids

In aspects, anti-inflammatory steroid components of compositionscomprise one or more steroid anti-inflammatory constituents. In aspects,a steroid anti-inflammatory constituent is a corticosteroidanti-inflammatory compound constituent.

In aspects, steroidal anti-inflammatory agent(s)/compound(s) suitablefor use in the compositions herein include can include an effectiveamount of any ophthalmologically suitable steroid anti-inflammatoryagent, including, e.g., 21-acetoxypregnenolone, alclometasone,algestone, amcinonide, beclomethasone, betamethasone, budesonide,chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol,corticosterone, cortisone, cortivazol, deflazacort, desonide,desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, enoxolone, fluazacort, flucloronide, flumethasone,flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl,fluocortolone, fluorometholone, fluperolone acetate, filuprednideneacetate, fluprednisolone, flurandrenolide, fluticasone propionate,formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortamate, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone,mometasone furoate, paramethasone, prednicarbate, prednisolone,prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate,prednisone, prednival, prednylidene, rimexolone, tixocortol,triamcinolone, triamcinolone acetonide, triamcinolone benetonide, and,e.g., triamcinolone hexacetonide, and pharmaceutically acceptable saltsthereof, and suitable mixtures of any or all thereof. Typically, acomposition will comprise ≤5, ≤3, or ≤2 anti-inflammatory steroids. Inaspects, a composition comprises ≤5, ≤3, or ≤2 anti-inflammatoryagents/compounds, overall.

In aspects, the steroid, e.g., corticosteroid anti-inflammatory compoundis any ophthalmologically suitable steroid, e.g., corticosteroidanti-inflammatory compounds demonstrating suitable therapeutic efficacyin treating inflammation or one or more conditions related toinflammation such as, e.g., redness, pain, discomfort, or the like. Inaspects, a steroidal, e.g., corticosteroidal, compound is anyophthalmologically suitable derivative, salt, hydrate, solvate, ether,ester, acetal, or ketal thereof.

In aspects, a corticosteroid anti-inflammatory for use in thecompositions herein include triamcinolone, prednisolone,methylprednisolone, betamethasone, dexamethasone, fluorometholone,fluocinolone, loteprednol, etc.

In aspects, compositions comprise between about 0.01-5 wt. % of asteroid anti-inflammatory compound, such as a corticosteroid compound,such as, e.g., between ˜0.01-˜4.5 wt. %, ˜0.01-˜4 wt. %, ˜0.01-˜3.5 wt.%, ˜0.01-˜3 wt. %, 0.01-2.5 wt. %, ˜0.01-2 wt. %, ˜0.01-1.5 wt. %,˜0.01-˜ wt. %, ˜0.01-˜0.5 wt. % such as, e.g., between ˜0.5-˜5 wt. %,˜1-˜5 wt. %, ˜1.5-˜5 wt. %, ˜2-˜5 wt. %, ˜2.5-˜5 wt. %, ˜3-˜5 wt. %,˜3.5-˜5 wt. %, ˜4-˜5 wt. %, ˜4.5-˜5 wt. %, as in, for example, between˜0.02-˜4.5 wt. %, ˜0.04-˜4 wt. %, ˜0.6-˜3.5 wt. %, ˜0.8-˜3 wt. %,˜1-˜2.5 wt. %, ˜1.2-˜2 wt. %, ˜1.2-˜1.8 wt. %, or, e.g., ˜1.2-˜1.6 wt.%, such as, e.g., about 1.5 wt. % of a steroid anti-inflammatorycompound. In aspects, the steroid anti-inflammatory compound is acorticosteroid compound.

In aspects, compositions comprise between about 1-50 mg/mL of a steroidanti-inflammatory compound, such as a corticosteroid compound, e.g.,between ˜1-˜45 mg/mL, ˜1-˜40 mg/mL, ˜1-˜35 mg/mL, ˜1-˜30 mg/mL, 1-˜25mg/mL, ˜1-˜20 mg/mL, such as ˜1-˜15 mg/mL, as in, e.g., between ˜5-˜50mg/mL, ˜10-˜50 mg/mL, or ˜15-˜50 mg/mL, as in, for example, between˜5-˜45 mg/mL, ˜6-˜40 mg/mL, ˜7-˜35 mg/mL, ˜8-˜30 mg/mL, ˜9-˜25 mg/mL,˜10-20 mg/mL, ˜12-18 mg/mL, ˜14-16 mg/mL, or, e.g., about 15 mg/mL of asteroid anti-inflammatory compound. In aspects, the steroidanti-inflammatory compound is a corticosteroid compound.

Triamcinolone

In certain aspects, compositions provided by the invention comprise,e.g., an anti-inflammatory steroid component of compositions provided bythe invention comprise, mostly comprise, generally consist of, orconsist of an ophthalmologically suitable derivative of prednisolone. Inaspects, the derivative of prednisolone is a triamcinolone compound. Inaspects, a triamcinolone compound is one of less than 5, such as one of2 or 3 anti-inflammatory compounds or anti-inflammatory steroids in acomposition.

In aspects, the anti-inflammatory agent is a triamcinolone compound. Atriamcinolone compound will comprise triamcinolone or a similar compoundthat exhibits DOS synthetic similar immunosuppressive andanti-inflammatory activity as to triamcinolone (e.g., activation of theglucocorticoid receptor, preventing the synthesis of prostaglandins andleukotrienes, inhibiting pro-inflammatory cytokines such as interleukin(IL)-1 and IL-6, inhibiting activation of T-lymphocytes, or acombination of any or all thereof. In aspects, the triamcinolonecompound is any ophthalmologically suitable triamcinolone compound suchas any ophthalmologically suitable derivative, salt, solvate, hydrate,enantiomer, polymorph, or prodrug thereof. In aspects, the triamcinolonecompound is triamcinolone acetonide (9-Fluoro-111P, 16a, 17,21-tetrahydroxypregna-1, 4-diene-3, 20-dione cyclic 16, 17-acetal withacetone).

Triamcinolone Amount

According to aspects, the invention provides an ophthalmologicallysuitable composition comprising an effective amount of triamcinolonecompound(s), such as, e.g., triamcinolone acetonide, wherein theophthalmologically suitable triamcinolone compound is present in thecomposition in an amount of between about 0.01-5 wt. %, such as, e.g.,between ˜0.01-˜4.5 wt. %, ˜0.01-˜4 wt. %, ˜0.01-˜3.5 wt. %, ˜0.01-˜3 wt.%, 0.01-2.5 wt. %, ˜0.01-2 wt. %, ˜0.01-1.5 wt. %, ˜0.01-1 wt. %,˜0.01-˜0.5 wt. % such as, e.g., between ˜0.5-˜5 wt. %, ˜1-˜5 wt. %,˜1.5-˜5 wt. %, ˜2-˜5 wt. %, ˜2.5-˜5 wt. %, ˜3-˜5 wt. %, ˜3.5-˜5 wt. %,˜4-˜5 wt. %, ˜4.5-˜5 wt. %, as in, for example, between ˜0.02-˜4.5 wt.%, ˜0.04-˜4 wt. %, ˜0.6-˜3.5 wt. %, ˜0.8-˜3 wt. %, ˜1-˜2.5 wt. %,˜1.2-˜2 wt. %, ˜1.2-˜1.8 wt. %, or, e.g., ˜1.2-˜1.6 wt. %, such as,e.g., about 1.5 wt. %. In aspects, the triamcinolone compound istriamcinolone acetonide.

In aspects, compositions comprise between about 1-50 mg/mL of atriamcinolone compound, such as, e.g., triamcinolone acetonide, such asin an amount between ˜1-˜45 mg/mL, ˜1-˜40 mg/mL, ˜1-˜35 mg/mL, 1-˜30mg/mL, 1-˜25 mg/mL, ˜1-˜20 mg/mL, such as ˜1-15 mg/mL, as in, e.g.,between ˜5-˜50 mg/mL, ˜10-˜50 mg/mL, or ˜15-˜50 mg/mL, as in, forexample, between ˜5-˜45 mg/mL, ˜6-˜40 mg/mL, ˜7-˜35 mg/mL, ˜8-˜30 mg/mL,˜9-˜25 mg/mL, ˜10-˜20 mg/mL, ˜12-˜18 mg/mL, ˜14-˜16 mg/mL, or, e.g.,about 15 mg/mL of a triamcinolone compound. In aspects, thetriamcinolone compound is triamcinolone acetonide.

In general, an “effective amount” of an API of a composition, or acomposition overall, as exemplified/discussed elsewhere, is an amountthat is suitable for causing a significant therapeutic effect in asubject, such as a human patient. As discussed below, “efficacy” and“effectiveness” in terms of excipients and other ingredients isdetermined by a measurable or significant effect of thecomponent/excipient for such a component's/ingredient's intendedpurpose.

According to aspects, compositions comprise triamcinolone plus one ormore additional anti-inflammatory agents, such as any one or moreanti-inflammatory agents described herein, including steroidal or NSAIDanti-inflammatory agents.

Prednisolone

In certain aspects, compositions provided by the invention comprise,e.g., an anti-inflammatory steroid component of compositions provided bythe invention comprise, mostly comprise, generally consist of, consistessentially of, or consist of a prednisolone compound. In aspects, aprednisolone compound is one of less than 5, such as one of 2 or 3anti-inflammatory compounds or anti-inflammatory steroids in acomposition. In aspects, a prednisolone compound will have at least twotimes, at least three, or even about five times or more of theanti-inflammatory potency of hydrocortisone. In aspects, a prednisolonecompound DOS inhibits edema and fibrin disposition, phagocyticmigration, capillary proliferation and deposition of collagen and scartissue. In aspects, the prednisolone compound is any ophthalmologicallysuitable prednisolone compound such as any ophthalmologically suitablederivative, salt, solvate, hydrate, enantiomer, polymorph, or prodrugthereof. In aspects, prednisolone derivatives can comprise, e.g.,rimexolone, difluprednate, various hydroxylation-related modificationsof prednisolone (see, e.g., Mohamed, et. al. in “Biotransformation ofprednisolone to hydroxy derivatives by Penicillium aurantiacum,” Biocatand Biotrans, 23 Apr. 2017, pp 215-222); modifications to prednisoloneon the cyclic acetal ring, such as those described in DE4129535; furthermodifications to such derivatives at the C-21 hydroxy group as isdescribed in, e.g., U.S. Pat. No. 5,733,901 (Gutterer); modifications atthe 16- and 17-carbon positions as is described by, e.g., Lee, et. al.in “New steroidal anti-inflammatory agents: prednisolone derivativeswith an isooxazoline fusion at the 16- and 17-carbons and an alkylcarboxylate at the 16 alpha-position,” Drugs Eps Clin Res. 1998;24(2):57-66, etc. In aspects, a prednisolone compound does not includetriamcinolone or a compound that is more structurally related totriamcinolone than prednisolone. In aspects, the prednisolone compoundis prednisolone acetate ([2-[(8S,9S,10R,11S,13S,14S,17R)-11,17-Dihydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl]acetate).

Prednisolone Amount

According to aspects, the invention provides an ophthalmologicallysuitable composition comprising an effective amount of prednisolonecompound(s), such as, e.g., prednisolone acetate, wherein theophthalmologically suitable prednisolone compound is present in thecomposition in an amount of between about 0.01-5 wt. %, such as, e.g.,between ˜0.01-˜4.5 wt. %, ˜0.01-˜4 wt. %, ˜0.01-˜3.5 wt. %, ˜0.01-˜3 wt.%, 0.01-2.5 wt. %, ˜0.01-2 wt. %, ˜0.01-1.5 wt. %, ˜0.01-˜ wt. %,˜0.01-˜0.5 wt. % such as, e.g., between ˜0.5-˜5 wt. %, ˜1-˜5 wt. %,˜1.5-˜5 wt. %, ˜2-˜5 wt. %, ˜2.5-˜5 wt. %, ˜3-˜5 wt. %, ˜3.5-˜5 wt. %,˜4-˜5 wt. %, ˜4.5-˜5 wt. %, as in, for example, between ˜0.02-˜4.5 wt.%, ˜0.04-˜4 wt. %, ˜0.6-˜3.5 wt. %, ˜0.8-˜3 wt. %, ˜1-˜2.5 wt. %,˜1.2-˜2 wt. %, ˜1.2-˜1.8 wt. %, or, e.g., ˜1.2-˜1.6 wt. %, such as,e.g., about 1.5 wt. %. In aspects, the prednisolone compound isprednisolone acetate.

In aspects, compositions comprise between about 1-50 mg/mL of aprednisolone compound, such as, e.g., prednisolone acetate, such as anamount of between ˜1-˜45 mg/mL, ˜1-˜40 mg/mL, ˜1-˜35 mg/mL, ˜1-˜30mg/mL, ˜1-˜25 mg/mL, ˜1-˜20 mg/mL, such as ˜1-15 mg/mL, as in, e.g.,between ˜5-˜50 mg/mL, ˜10-˜50 mg/mL, or ˜15-˜50 mg/mL, as in, forexample, between ˜5-˜45 mg/mL, ˜6-˜40 mg/mL, ˜7-˜35 mg/mL, ˜8-˜30 mg/mL,˜9-25 mg/mL, ˜10-20 mg/mL, ˜12-18 mg/mL, ˜14-16 mg/mL, or, e.g., about15 mg/mL of a prednisolone compound. In aspects, the prednisolonecompound is prednisolone acetate.

In general, an “effective amount” of an API of a composition, or acomposition overall, as exemplified/discussed elsewhere, is an amountthat is suitable for causing a significant therapeutic effect in asubject, such as a human patient. As discussed below, “efficacy” and“effectiveness” in terms of excipients and other ingredients isdetermined by a measurable or significant effect of thecomponent/excipient for such a component's/ingredient's intendedpurpose.

According to aspects, compositions comprise prednisolone plus one ormore additional anti-inflammatory agents, such as any one or moreanti-inflammatory agents described herein, including steroidal ornon-steroidal anti-inflammatory agents. In aspects, compositionscomprise prednisolone plus one or more additional non-steroidal agents.In aspects, compositions comprise prednisolone plus bromfenac.

Loteprednol

In certain aspects, compositions provided by the invention comprise,e.g., an anti-inflammatory steroid component of compositions provided bythe invention comprise, mostly comprise, generally consist of, consistessentially of, or consist of a loteprednol compound. In aspects, aloteprednol compound is one of less than 5, such as one of 2 or 3anti-inflammatory compounds or anti-inflammatory steroids in acomposition. In aspects, a loteprednol compound can be characterized onthe basis of being at least 2, at least 3, or all of the following—a17alpha-hydroxy steroid, an androstanoid, an organochlorine compound, asteroid acid ester, or a 3-oxo-Delta(1), Delta(4)-steroid, and exhibitscorticosteroid hormone receptor agonist activity. In aspects, theloteprednol compound is any ophthalmologically suitable loteprednolcompound such as any ophthalmologically suitable derivative, salt,solvate, hydrate, enantiomer, polymorph, or prodrug thereof. In aspects,the loteprednol compound is loteprednol etabonate. Loteprednol etabonateis the etabonate salt form of loteprednol.

Loteprednol Amount

According to aspects, the invention provides an ophthalmologicallysuitable composition comprising an effective amount of loteprednolcompound(s), such as, e.g., loteprednol etabonate, wherein theophthalmologically suitable loteprednol compound is present in thecomposition in an amount of between about 0.01-5 wt. %, such as, e.g.,between ˜0.01-˜4.5 wt. %, ˜0.01-˜4 wt. %, ˜0.01-˜3.5 wt. %, ˜0.01-˜3 wt.%, 0.01-2.5 wt. %, ˜0.01-2 wt. %, ˜0.01-1.5 wt. %, ˜0.01-˜ wt. %,˜0.01-˜0.5 wt. % such as, e.g., between ˜0.5-˜5 wt. %, ˜1-˜5 wt. %,˜1.5-˜5 wt. %, ˜2-˜5 wt. %, ˜2.5-˜5 wt. %, ˜3-˜5 wt. %, ˜3.5-˜5 wt. %,˜4-˜5 wt. %, ˜4.5-˜5 wt. %, as in, for example, between ˜0.02-˜4.5 wt.%, ˜0.04-˜4 wt. %, ˜0.6-˜3.5 wt. %, ˜0.8-˜3 wt. %, ˜1-˜2.5 wt. %,˜1.2-˜2 wt. %, ˜1.2-˜1.8 wt. %, or, e.g., ˜1.2-˜1.6 wt. %, such as,e.g., about 1.5 wt. %. In aspects, the loteprednol compound isloteprednol etabonate.

In aspects, compositions comprise between about 1-50 mg/mL of aloteprednol compound, such as, e.g., loteprednol etabonate, such as anamount of between ˜1-˜45 mg/mL, ˜1-˜40 mg/mL, ˜1-˜35 mg/mL, ˜1-˜30mg/mL, ˜1-˜25 mg/mL, ˜1-˜20 mg/mL, such as ˜1-15 mg/mL, as in, e.g.,between ˜5-˜50 mg/mL, ˜10-˜50 mg/mL, or ˜15-˜50 mg/mL, as in, forexample, between ˜5-˜45 mg/mL, ˜6-˜40 mg/mL, ˜7-˜35 mg/mL, ˜8-˜30 mg/mL,˜9-˜25 mg/mL, ˜10-20 mg/mL, ˜12-18 mg/mL, ˜14-16 mg/mL, or, e.g., about15 mg/mL of a loteprednol compound. In aspects, the loteprednol compoundis loteprednol etabonate.

In general, an “effective amount” of an API of a composition, or acomposition overall, as exemplified/discussed elsewhere, is an amountthat is suitable for causing a significant therapeutic effect in asubject, such as a human patient. As discussed below, “efficacy” and“effectiveness” in terms of excipients and other ingredients isdetermined by a measurable or significant effect of thecomponent/excipient for such a component's/ingredient's intendedpurpose.

According to aspects, compositions comprise loteprednol plus one or moreadditional anti-inflammatory agents, such as any one or moreanti-inflammatory agents described herein, including steroidal ornon-steroidal anti-inflammatory agents.

Non-Steroid

In aspects, compositions comprise, e.g., an anti-inflammatory steroidcomponent of a composition comprises, e.g., one or more non-steroidalanti-inflammatory constituents (agents, compounds). The term“constituents” is sometimes used in this disclosure to refer toingredients of a composition. Uncontradicted, it has the same meaning asagent/compound. In some aspects, anti-inflammatory steroid component(s)comprise at least one steroidal anti-inflammatory constituent and atleast one non-steroidal anti-inflammatory constituent.

In one aspect, the invention provides compositions comprising one ormore pharmaceutically acceptable and ophthalmologically suitablenon-steroidal anti-inflammatory compounds, such as, e.g., aspirin,benoxaprofen, benzofenac, bromfenac, bucloxic acid, butibufen,carprofen, cicloprofen, cinmetacin, clidanac, clopirac, diclofenac,diflupredinate, etodolac, fenbufen, fenclofenac, fenclorac, fenoprofen,fentiazac, flunoxaprofen, furaprofen, flurbiprofen, furobufen,furofenac, ibuprofen, ibufenac, indomethacin, indoprofen, isoxepac,ketroprofen, lactorolac, lonazolac, metiazinic, miroprofen, nepafenac,naproxen, norketotifen, oxaprozin, oxepinac, phenacetin, pirprofen,pirazolac, protizinic acid, sulindac, suprofen, tiaprofenic acid,tolmetin, and, e.g., zomepirac, and pharmaceutically acceptable saltsthereof, and mixtures thereof.

In aspects, anti-inflammatory steroid components of compositionsprovided by the invention comprise non-steroidal anti-inflammatorycompound(s) in an amount representing between about 0.01-0.2 wt. % ofthe composition, such as, e.g., between ˜0.01-0.1 wt. %, ˜0.01-˜0.09 wt.%, ˜0.01-˜0.08 wt. %, ˜0.01-˜0.07 wt. %, ˜0.01-0.06% wt. %, ˜0.01-0.05wt. %, ˜0.01-0.04 wt. %, ˜0.01-0.03 wt. %, ˜0.01-˜0.02 wt. %, such as,e.g., between ˜0.02-˜0.2 wt. %, ˜0.03-˜0.2 wt. %, ˜0.04-˜0.2 wt. %,˜0.05-˜0.2 wt. %, ˜0.06-˜0.2 wt. %, ˜0.07-˜0.2 wt. %, ˜0.08-˜0.2 wt. %,˜0.09-˜0.2 wt. %, ˜0.1-˜0.2 wt. %, as in, for example, between˜0.02-˜0.19 wt. %, ˜0.03-˜0.18 wt. %, ˜0.04-˜0.17 wt. %, ˜0.05-˜0.16 wt.%, ˜0.06-˜0.15 wt. %, ˜0.07-˜0.14 wt. %, ˜0.08-˜0.13 wt. %, ˜0.08-˜0.12wt. %, ˜0.08-˜0.11 wt. %, ˜0.08-˜0.1 wt. %, or, e.g., about 0.09 wt. %of a non-steroidal anti-inflammatory compound.

In aspects, compositions comprise between about 0.1-2 mg/mL of anon-steroidal anti-inflammatory compound, such as, e.g., between˜0.1-˜1.9 mg/mL, ˜0.1-˜1.8 mg/mL, ˜0.1-˜1.7 mg/mL, ˜0.1-˜1.6 mg/mL,˜0.1-˜1.5 mg/mL, ˜0.1-˜1.4 mg/mL, ˜0.1-˜1.3 mg/mL, ˜0.1-˜1.2 mg/mL,˜0.1-˜1.1 mg/mL, ˜0.1-˜1 mg/mL, ˜0.1-˜0.9 mg/mL, or, such as, e.g.,between ˜0.2-˜2 mg/mL, ˜0.3-˜2 mg/mL, ˜0.4-˜2 mg/mL, ˜0.5-˜2 mg/mL,˜0.6-˜2 mg/mL, ˜0.7-˜2 mg/mL, ˜0.8-˜2 mg/mL, ˜0.9-˜2 mg/mL, as in, forexample, between ˜0.2-˜1.9 mg/mL, ˜0.3-˜1.8 mg/mL, ˜0.4-˜1.7 mg/mL,˜0.5-˜1.6 mg/mL, ˜0.6-˜1.5 mg/mL, ˜0.7-˜1.4 mg/mL, ˜0.8-˜1.3 mg/mL,˜0.8-˜1.2 mg/mL, ˜0.08-˜1.1 mg/mL, ˜0.08-˜1 mg/mL, or, e.g., about 0.9mg/mL of a non-steroidal anti-inflammatory compound.

Bromfenac

In aspects, compositions provided by the invention comprise, e.g., ananti-inflammatory steroid component of compositions provided by theinvention comprise, a bromfenac compound. In aspects, the bromfenaccompound is a nonsteroidal anti-inflammatory drug (NSAID) with analgesicand anti-inflammatory activities that binds to and inhibits the activityof cyclooxygenase II (COX II), thereby inhibiting prostaglandinformation. In aspects, an effective amount of a bromfenac compounds DOSprevents vasodilation, leukocytosis, disruption of the blood-aqueoushumor barrier, an increase in vascular permeability and an increase inintraocular pressure (IOP). In aspects, the bromfenac compound is anyophthalmologically suitable bromfenac compound such as anyophthalmologically suitable derivative, salt, solvate, hydrate,enantiomer, polymorph, or prodrug thereof. In aspects, the bromfenaccompound is bromfenac sodium sesquihydrate. In aspects, the bromfenaccompound is bromfenac sodium salt sesquihydrate (the sesquihydrate ofthe sodium salt of bromfenac) (disodium;2-[2-amino-3-(4-bromobenzoyl)phenyl]acetate; trihydrate).

Bromfenac Amount

In aspects, anti-inflammatory steroid components of compositionsprovided by the invention comprise a bromfenac compound, such as, e.g.,bromfenac sodium sesquihydrate in an amount representing between about0.01-0.2 wt. % of the composition, such as, e.g., between ˜0.01-0.1 wt.%, ˜0.01-˜0.09 wt. %, ˜0.01-˜0.08 wt. %, ˜0.01-˜0.07 wt. %, ˜0.01-0.06%wt. %, ˜0.01-0.05 wt. %, ˜0.01-0.04 wt. %, ˜0.01-0.03 wt. %, ˜0.01-˜0.02wt. %, such as, e.g., between ˜0.02-˜0.2 wt. %, ˜0.03-˜0.2 wt. %,˜0.04-˜0.2 wt. %, ˜0.05-˜0.2 wt. %, ˜0.06-˜0.2 wt. %, ˜0.07-˜0.2 wt. %,˜0.08-˜0.2 wt. %, ˜0.09-˜0.2 wt. %, ˜0.1-˜0.2 wt. %, as in, for example,between ˜0.02-˜0.19 wt. %, ˜0.03-˜0.18 wt. %, ˜0.04-˜0.17 wt. %,˜0.05-˜0.16 wt. %, ˜0.06-˜0.15 wt. %, ˜0.07-˜0.14 wt. %, ˜0.08-˜0.13 wt.%, ˜0.08-˜0.12 wt. %, ˜0.08-˜0.11 wt. %, ˜0.08-˜0.1 wt. %, or, e.g.,about 0.09 wt. % of a bromfenac compound. In aspects, the bromfenaccompound is bromfenac sodium sesquihydrate.

In aspects, compositions comprise between about 0.1-2 mg/mL of abromfenac compound, such as bromfenac sodium sesquihydrate, such as,e.g., between ˜0.1-˜1.9 mg/mL, ˜0.1-˜1.8 mg/mL, ˜0.1-˜1.7 mg/mL,˜0.1-˜1.6 mg/mL, ˜0.1-˜1.5 mg/mL, ˜0.1-˜1.4 mg/mL, ˜0.1-˜1.3 mg/mL,˜0.1-˜1.2 mg/mL, ˜0.1-˜1.1 mg/mL, ˜0.1-˜1 mg/mL, ˜0.1-˜0.9 mg/mL, or,such as, e.g., between ˜0.2-˜2 mg/mL, ˜0.3-˜2 mg/mL, ˜0.4-˜2 mg/mL,˜0.5-˜2 mg/mL, ˜0.6-˜2 mg/mL, ˜0.7-˜2 mg/mL, ˜0.8-˜2 mg/mL, ˜0.9-˜2mg/mL, as in, for example, between ˜0.2-˜1.9 mg/mL, ˜0.3-˜1.8 mg/mL,˜0.4-˜1.7 mg/mL, ˜0.5-˜1.6 mg/mL, ˜0.6-˜1.5 mg/mL, ˜0.7-˜1.4 mg/mL,˜0.8-˜1.3 mg/mL, ˜0.8-˜1.2 mg/mL, ˜0.08-˜1.1 mg/mL, ˜0.08-˜1 mg/mL, or,e.g., about 0.9 mg/mL of a bromfenac compound. In aspects, the bromfenaccompound is bromfenac sodium sesquihydrate.

In general, an “effective amount” of an API of a composition, or acomposition overall, as exemplified/discussed elsewhere, is an amountthat is suitable for causing a significant therapeutic effect in asubject, such as a human patient. As discussed below, “efficacy” and“effectiveness” in terms of excipients and other ingredients isdetermined by a measurable or significant effect of thecomponent/excipient for such a component's/ingredient's intendedpurpose.

According to aspects, compositions comprise bromfenac plus one or moreadditional anti-inflammatory agents, such as any one or moreanti-inflammatory agents described herein, including steroidal ornon-steroidal anti-inflammatory agents. In aspects, compositionscomprise bromfenac plus one or more additional steroidal agents. Inaspects, compositions comprise bromfenac plus prednisolone.

Antimicrobial+Anti-Inflammatory Compounds

In aspects, compositions comprise both a therapeutically effectiveamount of a quinolone antibiotic component and a therapeuticallyeffective amount of an anti-inflammatory steroid component. In aspects,compositions comprise a therapeutically effective amount of abroad-spectrum quinolone antibiotic component, such as, e.g., inspecific aspects a broad-spectrum antibiotic compound, and atherapeutically effective amount of one or more steroidal ornon-steroidal agents.

In aspects, compositions comprise therapeutically effective amounts ofat least one ophthalmologically suitable fluoroquinolone antibioticcompound and at least on ophthalmologically suitable corticosteroidcompound, or ophthalmologically suitable salts, hydrates, solvates,ethers, esters, acetal, and ketals thereof. In aspects, compositions canbe characterized by the ratios of one component or compound to anothercomponent or compound, such as, e.g., a quinolone antibiotic componentconstituent(s) to an anti-inflammatory component constituent(s) (suchas, for example, a corticosteroid constituent). In aspects, compositionsprovide a quinolone antibiotic component and an anti-inflammatorycomponent in fixed amounts, such as, e.g., specific ratios. In aspects,compositions are reproducibly produced, and quality screened for thepresence of such amounts of such APIs prior to packaging, use, etc.

In aspects, the fluoroquinolone antibiotic compound is a moxifloxacincompound or a gatifloxacin compound. In aspects, the corticosteroidcomponent is a triamcinolone compound, a prednisolone compound, or aloteprednol compound. In aspects, an anti-inflammatory componentconstituent can be a non-steroidal anti-inflammatory compound, such as,e.g., a bromfenac compound. In aspects, compositions comprisetherapeutically effective amounts of moxifloxacin hydrochloride orgatifloxacin, and one or more of triamcinolone acetonide, prednisoloneacetate, and bromfenac sodium sesquihydrate.

Table 1 below provides exemplary composition ingredients, exemplaryranges of such ingredients, and exemplary ratios between them. Inaspects, compositions comprise exemplified ingredients in suchexemplified ratios.

TABLE 1 Exemplary Ingredients & Ratios. Description Name Exemplary rangeFluoroquinolone antibiotic Moxifloxacin  0.1-5 mg/mL Fluoroquinoloneantibiotic Gatifloxacin   1-10 mg/mL Steroid anti-inflammatoryTriamcinolone   1-50 mg/mL Steroid anti-inflammatory Prednisolone   1-50mg/mL Steroid anti-inflammatory Loteprednol   1-50 mg/mL Non-steroidanti-inflammatory Bromfenac  0.5-1 mg/mL Non-ionic suspension agent PEG3350  10-100 mg/mL Non-ionic suspension agent CMC   2-20 mg/mL Ionicsuspension agent Hyaluronic acid   2-20 mg/mL Non-ionic suspension agentPS-80   5-15 mg/mL present with one or more additional suspensionagents) Total Suspension Agent —   7-115 mg/mL Exemplary Ratios:Moxifloxacin : Suspension 1:1.4-1:1150 Component Gatifloxacin :Suspension 1:0.7-1:115 Component Fluroquinolone : Suspension1:0.7-1:1150 Component Fluoroquinolone: Ionic Suspension Component1:0.5-1:200 Fluoroquinolone : Non-Ionic Suspension Component1:0.7-1:1150 Steroid Anti-Inflammatory: Suspension Component1:0.14-1:115 Ionic Suspension Agent : Non-Ionic Suspension Agent1:0.35-1:57.5 Total API: Suspension 1:0.9-1:105 Component

In aspects, compositions comprise a ratio of fluoroquinolone antibioticcompound:suspension component of between about 1.07-about 1:1150, suchas, e.g., between about 1:0.7-about 1:115.

In aspects, compositions comprise a ratio of fluoroquinolone antibioticcompound:ionic suspension component of between about 1:0.5-about 1:200,such as, e.g., between about 1:100-about 1:1.

In aspects, compositions comprise a ratio of fluoroquinolone antibioticcompound:non-ionic suspension component of between about 1:0.7-about1:1150, such as, e.g., 1:1.2-about 1:1100.

In aspects, compositions comprise a ratio of steroid anti-inflammatorycompound:suspension component of between about 1:0.14-about 1:115, suchas, e.g., between about 1:0.24-about 1:115.

In aspects, compositions comprise a moxifloxacin compound and asuspension component, wherein the ratio of the moxifloxacin to thesuspension component, is, e.g., between about 1:40-about 1:1, such as,e.g., between ˜1:38-˜1:4, ˜1:36-˜1:8, ˜1:34-˜1:10, or, e.g.,˜1:36-˜1:12, such as, e.g., between about 1:30-1:2. In aspects,compositions comprise a moxifloxacin compound an ionic suspension agent,wherein the ratio of the moxifloxacin compound to the ionic suspensionagent is between about 1:30-about 1:1, or, e.g., 1:20-˜1:2. In aspects,compositions comprise a moxifloxacin compound and a non-ionic suspensionagent, wherein the ratio of the moxifloxacin compound to the non-ionicsuspension agent is, e.g., between about 1:20-about 1:2, such as, e.g.,between about 1:5-about 1:4, such as, e.g., ˜1:12-˜1:8, such as, e.g.,about 1:10. In aspects, compositions comprise a non-ionic suspensionagent and an ionic suspension agent, wherein the ratio of the non-ionicsuspension agent to the ionic suspension agent is between ˜1:10-about1:0.1, e.g., about 1:9-about 1:0.2 (or, e.g., stated alternatively about5:1), or, e.g., about 1:8-about 1:0.25 (or, stated alternatively, about4:1).

In aspects, compositions comprise a gatifloxacin compound and asuspension component, wherein the ratio of the gatifloxacin to thesuspension component, is, e.g., between about 1:10-about 1:0.1, e.g.,˜1:8-˜1:1, ˜1:7-˜1:2, or, e.g., ˜1:6-˜1:3. In aspects, compositionscomprise a gatifloxacin compound an ionic suspension agent, wherein theratio of the gatifloxacin compound to the ionic suspension agent isbetween about 1:6-about 1:0.8, e.g., ˜1:5-˜1:0.6, or, e.g., ˜1:4-˜1:0.4.In aspects, compositions comprise a gatifloxacin compound and anon-ionic suspension agent, wherein the ratio of the gatifloxacincompound to the non-ionic suspension agent is, e.g., between about1:4-about 1:1, e.g., ˜1:3-about 1:1, ˜1:2.5-˜1:1, such as, e.g., ˜1:2.In aspects, compositions comprise a non-ionic suspension agent and anionic suspension agent, wherein the ratio of the non-ionic suspensionagent to the ionic suspension agent is between ˜1:10-about 1:0.1, e.g.,about 1:9-about 1:0.2 (or, e.g., stated alternatively about 5:1), or,e.g., about 1:8-about 1:0.25 (or, stated alternatively, about 4:1).

In aspects, the quinolone antibiotic component present within acomposition does not detectably or significantly impact the efficacy,e.g., the anti-inflammatory activity or effect, of the anti-inflammatorysteroid component of the composition. In aspects, the anti-inflammatorysteroid component present within the composition does not detectably orsignificantly impact the efficacy, e.g., the antimicrobial inhibition orkilling strength or activity of, the quinolone antibiotic component ofthe composition. In aspects no quinolone antibiotic componentconstituent(s) in the composition(s) cause(s) a detectable orsignificant detrimental impact to the recipient, such as, e.g., one ormore unintended side effect(s), e.g., due to the copresence of thequinolone antibiotic component and anti-inflammatory steroid component,and anti-inflammatory steroid component constituent(s) present in thecomposition(s) cause(s) a detectable or significant detrimental impactto the recipient, such as, e.g., one or more unintended side effects),e.g., due to the copresence of quinolone antibiotic component andanti-inflammatory steroid component.

The quinolone antibiotic component or the anti-inflammatory steroidcomponent can enhance the activity of the other or, in aspects, can actsynergistically in treating or preventing clinically significant levelsof infection, irritation (e.g., pain, redness, swelling, itching,discomfort, discharge, etc.), or both related to an infectiousophthalmic condition. For example, in aspects, administering the twocomponents together provide a detectable or significant increase in thelevel of inflammation associated with an ocular infection over that ofeither component administered alone (such as, e.g., by reducing thelevel of infection causing the inflammation and co-treating existinginflammation).

In aspects, compositions comprise between about 0.01-about 1 wt. %, suchas, e.g., about 0.1 wt. % of a moxifloxacin compound, such as, e.g.,moxifloxacin hydrochloride, and between about 0.01-about 5 wt. %, e.g.,about 1.5 wt. % of a triamcinolone compound, such as, e.g.,triamcinolone acetonide.

In aspects, compositions comprise between 0.01-about 1 wt. %, such as,e.g., about 0.1 wt. % of a moxifloxacin compound, such as, e.g.,moxifloxacin hydrochloride, and between about 0.01-about 5 wt. %, e.g.,about 1.5 wt. % of a prednisolone compound, such as, e.g., prednisoloneacetate.

In aspects, compositions comprise between about 0.01-about 1 wt. %, suchas, e.g., about 0.1 wt. % of a moxifloxacin compound, such as, e.g.,moxifloxacin hydrochloride, and between about 0.01-about 5 wt. %, e.g.,about 1.5 wt. % of a loteprednol compound, such as, e.g., loteprednoletabonate.

In aspects, compositions comprise between about 0.01-about 2 wt. %, suchas, e.g., about 0.5 wt. % of a gatifloxacin compound, between about0.01-about 5 wt. %, e.g., about 1.5 wt. % of a prednisolone compound,such as, e.g., prednisolone acetate, and between about 0.01-about 0.2wt. %, such as, e.g., about 0.09 wt. % of a bromfenac compound, such as,e.g., bromfenac sodium sesquihydrate.

In aspects, compositions comprise between about 0.01-about 1 wt. %, suchas, e.g., about 0.1 wt. % of a moxifloxacin compound, such as, e.g.,moxifloxacin hydrochloride, between about 0.01-about 5 wt. %, e.g.,about 1.5 wt. % of a prednisolone compound, such as, e.g., prednisoloneacetate, and between about 0.01-about 0.2 wt. %, such as, e.g., about0.09 wt. % of a bromfenac compound, such as, e.g., bromfenac sodiumsesquihydrate.

In aspects, compositions herein comprise at least one fluoroquinoloneantimicrobial compound and at least one steroid anti-inflammatorycompound. In aspects, the fluoroquinolone compound is moxifloxacin orgatifloxacin. In aspects, the steroid anti-inflammatory compound istriamcinolone, prednisolone, or loteprednol.

In aspects, compositions comprise an amount of moxifloxacin of betweenabout 0.01-about 1 wt. % (about 0.1-about 5 mg/mL), such as about 0.1wt. % or about 1 mg/mL, and an amount of triamcinolone of between about0.01-about 5 wt. % (about 1-about 50 mg/mL), such as about 1.5 wt. % orabout 15 mg/mL. In aspects, compositions comprise an amount ofmoxifloxacin of between about 0.01-about 1 wt. % (about 0.1-about 5mg/mL), such as about 0.1 wt. % or about 1 mg/mL, and an amount ofprednisolone of between about 0.01-about 5 wt. % (about 1-about 50mg/mL), such as about 1.5 wt. % or about 15 mg/mL. In aspects,compositions comprise an amount of moxifloxacin of between about0.01-about 1 wt. % (about 0.1-about 5 mg/mL), such as about 0.1 wt. % orabout 1 mg/mL, and an amount of loteprednol of between about 0.01-about5 wt. % (about 1-about 50 mg/mL), such as about 1.5 wt. % or about 15mg/mL. In aspects, compositions described in this paragraph can furthercomprise a non-steroid anti-inflammatory compound. In aspects, thenon-steroid anti-inflammatory compound is bromfenac. In aspects,compositions here can comprise between about 0.1-about 0.1 wt. % (about0.1-about 2 mg/mL), such as, e.g., about 0.09 wt. % or about 0.9 mg/L.

In aspects, compositions comprise an amount of gatifloxacin of betweenabout 0.01-about 1 wt. % (about 1-about 10 mg/mL), such as about 0.5 wt.% or about 5 mg/mL, and an amount of triamcinolone of between about0.01-about 5 wt. % (about 1-about 50 mg/mL), such as about 1.5 wt. % orabout 15 mg/mL. In aspects, compositions comprise an amount ofmoxifloxacin of between about 0.01-about 1 wt. % (about 0.1-about 5mg/mL), such as about 0.1 wt. % or about 1 mg/mL, and an amount ofprednisolone of between about 0.01-about 5 wt. % (about 1-about 50mg/mL), such as about 1.5 wt. % or about 15 mg/mL. In aspects,compositions comprise an amount of moxifloxacin of between about0.01-about 1 wt. % (about 0.1-about 5 mg/mL), such as about 0.1 wt. % orabout 1 mg/mL, and an amount of loteprednol of between about 0.01-about5 wt. % (about 1-about 50 mg/mL), such as about 1.5 wt. % or about 15mg/mL. In aspects, compositions described in this paragraph can furthercomprise a non-steroid anti-inflammatory compound. In aspects, thenon-steroid anti-inflammatory compound is bromfenac. In aspects,compositions here can comprise between about 0.1-about 0.1 wt. % (about0.1-about 2 mg/mL), such as, e.g., about 0.09 wt. % or about 0.9 mg/L.

Suspension Component

In aspects, compositions comprise one or more ophthalmologicallysuitable suspension component(s). In alternative aspects, compositionsprovided by the invention do not comprise any component characterizableas a suspension component. Herein, “suspension component” refers to asubstance used in the ophthalmic compositions to DOS maintain theactives in suspension within the composition(s), typically such that thecomposition(s) remain suitable for ocular administration for a DOSenhanced period of time (as compared to a corresponding formulationlacking the suspension component). In aspects, a suspension componentprovides one or more functions other than suspension functionality, suchas, e.g., providing DOS surfactant activity, DOS preservative activity,etc.

In aspects, a suspension component constituent is a surfactant orexhibits surface activity. E.g., in aspects a suspension component DOSreduces the interfacial tension between solid particles and a vehicle,e.g., between particles of one or more active ingredients (such as,e.g., between one or more anti-microbial component constituents, betweenone or more anti-inflammatory steroid component constituents, or both)and a vehicle such as water. In aspects, DOS reduction in interfacialtension between such particles and vehicle DOS promotes wetting anddeflocculation of such particles. In aspects, a suspension componentprovides a DOS reduction in contact angle between particle(s) andvehicle which DOS increases dissolution of one or more active agents,such as, e.g., increasing dissolution of one or more active agents by,e.g., at least about 1%, ≥˜1.5%, ≥˜2%, ≥˜2.5, ≥˜3%, ≥˜3.5%, ≥˜4%,≥˜4.5%, ≥˜5%, ≥˜5.5%, ≥˜6%, ≥˜6.5%, ≥˜7%, ≥˜7.5%, ≥˜8%, ≥˜8.5%, ≥˜9%,or, e.g., ≥˜9.5%, ≥˜10% or more. In aspects, as a result of increaseddissolution, a DOS greater amount of active penetrates the eye andimparts DOS therapeutic effect than compositions lacking such asuspension component. In aspects, composition(s) comprising a suspensioncomponent such as those described here, e.g., in specific aspectshyaluronic acid, carboxymethyl cellulose (CMC), polysorbate-80, or apolyethoxylated castor oil (e.g., Cremophor® EL) or a relatedcomposition (e.g., a hydrogenated polyethoxylated castor oil (e.g.,Cremophor® RH-40), or combinations thereof, DOS increase the quantity ofone or more active agents (e.g., one or more antimicrobial agents suchas a fluoroquinolone antibiotic, one or more anti-inflammatory agentssuch as a steroid or non-steroid anti-inflammatory agent, or acombination thereof) over compositions lacking such a suspension agentby at least 1%, ≥˜2.5, ≥˜3.5%, ≥˜4.5%, ≥˜5%, 6.5%, ≥˜7.5%, ≥˜9%, ≥˜9.5%,≥˜10%, ≥˜2.5%, ≥˜15%, ≥˜20%, ≥˜25%, or ≥˜33% (e.g., 5-100%, 5-75%, or5-50% or 10-300%, 10-200%, 10-150%, 10-100%, 10-70%, 10-50%, or 10-40%).

In aspects, compositions provided by the invention comprise a suspensioncomponent comprising suspension agent(s). In aspects, the suspensionagent is any ophthalmologically suitable suspension component capable ofmaintaining the ingredients of the composition in suspension such thatthe compositions remain suitable for ocular administration for a periodof at least about, e.g., 1 month or more, such as, e.g., ≥˜5 weeks, ≥˜6weeks, ≥˜7 weeks, ≥˜2 months (8 weeks), ≥˜9 weeks, ≥˜10 weeks, ≥˜11weeks, ≥˜3 months (12 weeks) or more, such as ≥˜4 months, ≥˜5 months,≥˜6 months, ≥˜7 months, ≥˜8 months, ≥˜9 months, ≥˜10 months, ≥˜11months, or, e.g., ≥˜12 months or more, such as ≥˜18 months. ≥˜2 years,≥˜32 months, or, e.g., ≥˜3 years or more.

In aspects, a suitable suspension component is any suspension componentcapable of maintaining both the quinolone antibiotic component andanti-inflammatory agent together in suspension without detectable orsignificant clumping, flocculation, caking (cake formation), undesirableAPI reactions/degradation, or coagulation for a period of at leastabout, e.g., 1 month or more, such as, e.g., ≥˜5 weeks, ≥˜6 weeks, ≥˜7weeks, ≥˜2 months (8 weeks), ≥˜9 weeks, ≥˜10 weeks, ≥˜11 weeks, ≥˜3months (12 weeks) or more, such as ≥˜4 months, ≥˜5 months, ≥˜6 months,≥˜7 months, ≥˜8 months, ≥˜9 months, ≥˜10 months, ≥˜11 months, or, e.g.,≥˜12 months or more, such as ≥˜18 months, ≥˜2 years, ≥˜32 months, or,e.g., ≥˜3 years or more.

In aspects, a suspension component can comprise at least 1, such as,e.g., ≥2, ≥3, ≥4, or, e.g., ≥5 suspension constituents (agents). Inaspects, compositions comprise a suspension component which comprises atleast 2 suspension constituents (e.g., agents). In aspects, compositionscomprise 2 suspension constituents (agents). In aspects, a suspensioncomponent comprises an ionic suspension constituent (agent). In aspects,a suspension component comprises a non-ionic suspension constituent(agent). In aspects, a suspension component comprises both an ionicsuspension component and a non-ionic suspension component.

In aspects, a suspension component can be any one or moreophthalmologically suitable suspension component constituent, such as,e.g., hyaluronic acid, methylcellulose, carboxymethylcellulose (CMC),hydroxyethylcellulose, hydroxypropyl methylcellulose, gelatin, acacia,povidone, polyvinylpyrrolidone, polysorbates (e.g., polysorbate-80), andpolyoxyl-ethylated castor oil (e.g., Cremophor® EL or Cremophor® RH-40),and polyethylene glycols (PEGs), such as, e.g., PEG 400, PEG 3350, etc.or any ophthalmologically suitable derivative, prodrug, hydrate, salt,solvate, enantiomer, or polymorph thereof. In aspects, a suspensioncomponent constituent can DOS enhance the suspension of one or moreactive ingredients (e.g., a quinolone antibiotic component constituent,and anti-inflammatory steroid component constituent, or both). Inaspects, a suspension component constituent can DOS increase suspensionof a composition when one or more other suspension components arepresent. For example, higher molecular weight PEGs (such as, e.g., PEG3350 and the like), or, e.g., acacia, povidone, povidone iodine, or PVP,can provide suspension activity and/or increase the viscosity of thecomposition, which can, alone or in combination with one or more othersuspension component constituents, DOS increase the suspension of one ormore active ingredient. In aspects, one or more PEGs can be present withone or more other suspension component constituents. In aspects, asuspension component constituent, e.g., acacia, povidone,povidone-iodine, PVP, or the like, DOS stabilizes a suspension (e.g.,maintains a suspension as a suspension for a DOS longer period of timethan a similar composition without the constituent). In aspects, asuspension component constituent stabilizes an emulsion, that is, actsas an emulsion stabilizer.

In aspects, a suspension component comprises at least one suspensionagent which is not characterizable as a solubilizing compound, such as,e.g., a compound which significantly increases the solubilization of oneor more active ingredients, such as, e.g., a fluoroquinolone antibioticcompound a steroid anti-inflammatory compound, a non-steroidanti-inflammatory compound, or a combination thereof. In aspects,compositions lacking such a suspension agent would be capable ofsolubilizing any active ingredient, such as, e.g., a fluoroquinoloneantibiotic compound a steroid anti-inflammatory compound, a non-steroidanti-inflammatory compound, or a combination thereof, to the same extent(e.g., to within ˜90%, ˜91%, ˜92%, ˜93%, ˜94%, ˜95%, ˜96%, ˜97%, ˜98%,˜99%, or, e.g., ˜100%) as that accomplished by the same compositioncomprising the suspension agent.

In aspects, the primary ionic suspension agent in the composition is nota solubilizing agent. In aspects, at least one of the suspension agentsis not a solubilizing agent/surfactant. In aspects, most of thesuspension component is not composed of solubilizingagent(s)/surfactant(s). In aspects, no part of the suspension componentis a surfactant. In aspects, any ionic suspension that is also asurfactant has a molecular weight of less than about 10,000 Da/10 kDa,e.g., less than about 8,000 Da, less than about 7,500 Da, less thanabout 6,000 Da, less than about 5,000 Da, less than about 3,500 Da, lessthan about 2,500 Da, or less than about 1,500 Da, such as, e.g., about1,000 Da-about 10,000 Da, e.g., about 1,250 Da-about 7,750 Da.

In aspects, any suspension agent that is also a surfactant has amolecular weight of at least 1,000 Da/1 kDa, such as at least about1,250 Da/1.25 kDa.

In aspects, a suspension agent is an FDA approved compound forophthalmic injections, such as, e.g., CMC, a hyaluronic acid (“HA”). Asdiscussed elsewhere, any reference to hyaluronic acid here includes anysuitable form of HA from any organism or synthetic source, derivatizedforms of HA, and salts of HA (e.g., sodium hyaluronate).

In aspects, compositions do not comprise a suspension agent which is notapproved by the FDA for ophthalmic injections.

In aspects, suspension components comprise at least one constituenthaving a naturally occurring receptor for the compound on ocularepithelial cells.

In aspects, a suspension agent comprises, mostly comprises, generallyconsists of, essentially consists of, or consists of a hyaluronic acidcomponent, formed from one or more HA compound(s). In aspects, a“hyaluronic acid component” is synonymous with a “hyaluronic acidcomposition”. In aspects, a “hyaluronic acid component” or “hyaluronicacid composition” can comprise one or more hyaluronic acid compounds.

In aspects, a suspension agent comprises, mostly comprises, generallyconsists of, consists essentially of, or consists of one or morecellulose compounds, e.g., one or more cellulose derivatives, such ascellulose ester/ether derivatives, such as CMC, hydroxyethylcellulose(HEC), methylcellulose (MC), and the like, such as salts thereof (e.g.,sodium CMC).

In aspects, a suspension agent comprises, mostly comprises, generallyconsists of, or is a polysorbate, such as, e.g., polysorbate-80. Inaspects, suspension agent(s) or suspension component or both (whethersimilar in structure to polysorbate-80 or not) (e.g., some, most,generally all or all suspension agents in a composition) has/havesuspension capabilities at least as great as 75% of the suspensioncapabilities of polysorbate-80, Cremophor RH40, or Cremophor EL. Inaspects, suspension agent(s) or suspension component or both (whethersimilar in structure to polysorbate-80 or not) (e.g., some, most,generally all or all suspension agents in a composition) has/havesuspension capabilities at least as great as 75% of the suspensioncapabilities of polysorbate-80. In aspects, suspension agent orsuspension component has suspension capabilities that are at leastsignificantly similar to polysorbate-80 or are DOS improved overpolysorbate-80. Examples of suitable suspending agents can, in aspects,include hyaluronic acid, carboxymethyl cellulose (e.g., sodium CMC),hydroxyethyl cellulose, hydroxypropyl methylcellulose,polyvinylpyrrolidone (PVP) (e.g., polyvinylpyrrolidone K90), PluronicF127, and carbomer. In aspects, the suspension component lacks anyeffective amount or any detectable amount of Pluronic F127, HPMC, orxanthan gum. In aspects, the suspension component lacks anycarbomer-type polymers (acrylic acid polymers). In aspects, thesuspension component comprises two or more suspension agents/compounds,which are together in the formulation. In aspects, the suspensioncomponent lacks any combination of suspension agents comprising two ormore of HA, CMC, HEC, HPMC.

In aspects, a suspension component comprises a polyoxyl-ethylated castoroil, such as a Cremophor® (e.g., Cremophor® EL or Cremophor® RH-40). Inaspects, the polyoxyl-ethylated castor oil contributes less than half ofthe suspension properties of the suspension component. In aspects, asuspension component comprises a polyoxyl-ethylated castor oil incombination with one or more additional suspension agents that exhibitDOS improved suspension effects as compared to the polyoxyl-ethylatedcastor oil.

In aspects, a suspension component does not comprise any one or more ofa co-polymer.

In aspects, a suspension component does not comprise any one or more ofa nonionic triblock copolymer. In aspects, a suspension component doesnot comprise a nonionic triblock copolymer composed of a centralhydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked bytwo hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Thatis, in aspects, a suspension component does not comprise one or more“poloxamer” agents (or any poloxamer agents), e.g., a Pluronic®, such asPluronic F127 or an equivalent thereof. In aspects, a suspensioncomponent herein does not comprise any one or more of a blockco-polymer. In aspects, a suspension component herein does not compriseany one or more of specific block copolymers. In aspects, a suspensioncomponent herein does not comprise non-ionic block copolymers. Inaspects, a suspension component herein does not comprise a non-ionicpolyoxyethylene-polyoxypropylene block copolymer having the chemicalstructure:HO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H,wherein x is an integer having the value of at least 8 (such as, e.g.,≥8, ≥9, ≥10, ≥11, ≥12 or more) and y is an integer having the value ofat least 38 (such as, e.g., ≥38, ≥39, ≥40, ≥41, ≥42, ≥43, ≥44, ≥45 ormore).In aspects, a suspension component does not comprise a polymer ofD-glucose units (e.g., linear linked beta-d-glucose backbone) comprisingtrisaccharide side chains. In aspects, a suspension component does notcomprise a polysaccharide having a trisaccharide side chain comprisingmannose units. In aspects, a suspension component does not comprise apolysaccharide having a trisaccharide side chain exhibiting two mannoseunits separated by guluronic acid. In aspects, a suspension componentdoes not comprise xanthan gum. In aspects, compositions do not comprisea hydrocolloid other than a cellulose derivative hydrocolloid, such as,e.g., in aspects, compositions herein do not comprise a suspensioncomponent comprising starch, xanthan, guar gum, locust bean gum, gumkaraya, gum tragacanth, or gum Arabic.

In certain aspects, compositions comprise a suspension component whichdoes not represent more than about 10% by mass of the composition. Inaspects, compositions comprise a suspension component which representsless than about 9%, such as, e.g., ≤˜8%, ≤˜7%, ≤˜6%, ≤˜5%, ≤˜4%, or,e.g., ≤˜3% by mass of a suspension component. E.g., in aspects, asuspension component makes up about 0.75-10%, e.g., ˜1-10%, ˜1.5-10%,˜1.5-9%, ˜2-8%, ˜2.5-7.5%, ˜2.5-5%, ˜2-6%, ˜2-5%, ˜2.54%, ˜2-4.5%,2-3.5%, or 2.5-3.5% of the composition. In aspects, the suspensioncomponent is an ionic suspension component described herein. In aspects,a suspension component is mostly, generally only, or only composed ofionic suspension agent(s). In aspects, the suspension componentcomprises an ionic and a non-ionic suspension component. In aspects, theionic suspension component contributes DOS more to the suspensionproperties of the suspension component than the non-ionic suspendingagent/suspension agent. In aspects, the suspension component comprises amixture of non-ionic suspension components. In aspects, one or moresuspension agents of a suspension component can be characterized as asurfactant or a solubilizer/dispersing agent, such as, e.g., polysorbate80, Solutol HS 15, Pluronic F68, Pluronic F127, Cremophor RH40,Cremophor EL, sodium glycocholate, etc. In aspects, the surfactantcomponent does not comprise an effective amount of a Poloxamer/Pluronicor similar agent (as described elsewhere) or lacks any such component.

Ionic Suspension Component

In aspects, compositions comprise a suspension component comprising oneor more ionic suspension agents (constituents), such as, e.g.,hyaluronic acid, carboxymethylcellulose, acacia gum, or anycombination/mixture thereof.

In aspects, an ionic suspension component comprises a suspension agenthaving a molecular weight greater than about 2500 kDa, such as, e.g., atleast 2600 kDa, ≥˜2800 kDa, ≥˜3000 kDa, ≥˜3200 kDa, ≥˜3400 kDa, ≥˜3600kDa, ≥˜3800 kDa, ≥˜4000 kDa, ≥˜4200 kDa, ≥˜4400 kDa, ≥˜4600 kDa, ≥˜4800kDa, ≥˜5000 kDa, or higher. In aspects, an ionic suspension componentcomprises a suspension agent having an average molecular weight of lessthan about 3000 kDa. In aspects, an ionic suspension component comprisesa suspension agent having an average molecular weight of at least 5000kDa.

In aspects, the composition lacks any stability agent that exhibitsthermosensitivity similar to or more than that of Pluronic F127. Inaspects, compositions of the invention are DOS more stable at 20-25degrees C. than compositions mostly or entirely comprising Pluronic F127as a suspension agent.

In aspects, compositions comprise an effective amount of hyaluronicacid, carboxymethylcellulose, acacia gum, or any combination/mixturethereof. In general, any compounds described herein by referenceinclude, at least in aspects, any suitable derivatives, prodrugs,hydrates, salts, solvates, enantiomers, or polymorphs thereof, such as,e.g., “hyaluronic acid” or “hyaluronic acid compound” can comprise“hyaluronate sodium” (“sodium hyaluronate”). In some aspects,compositions comprise only ionic suspension component constituents. Insome aspects, compositions comprise a suspension component comprisingboth ionic and non-ionic suspension component constituents. In aspects,the HA component DOS improves tear film stability, increasesconjunctival goblet cell density, protects against corneal epithelialcell damage, or exhibits a combination of some or all thereof. Inaspects, a composition comprising HA also comprises an effective amountof trehalose. In aspects, compositions are free of trehalose. Inaspects, the HA agent(s) of the composition exhibit DOS mucoadhesiveeffects (adherence of mucous membranes). In aspects, some, most, or allof the HA agent(s) are cross-linked. In aspects, some, most, or all ofthe HA agent(s) are not crosslinked. In aspects the HA exhibits DOShygroscopic/humectant effects. In aspects, the HA can bind at least 10×,at least 20×, at least 50×, at least 100×, at least 200×, at least 500×,or even at least 1000× its weight in water. In aspects HA agent(s)exhibit significant viscoelasticity. In aspects, inclusion of HAagent(s) or similar agent(s) render compositions that can be classifiedas hydrogels. In aspects, such compositions have increased API residencetime, DOS better/more diffusion through layers of the eye, or both.

In aspects, compositions comprise between about 1-40 mg/mL of an ionicsuspension component, such as, e.g., between ˜1-˜38 mg/mL, ˜1-˜36 mg/mL,˜1-˜34 mg/mL, ˜1-˜32 mg/mL, ˜1-˜30 mg/mL, ˜1-˜28 mg/mL, ˜1-˜26 mg/mL,˜1-˜24 mg/mL, ˜1-˜22 mg/mL, ˜1-˜24 mg/mL, ˜1-˜22 mg/mL, ˜1-˜20 mg/mL, asin, for example, between ˜1.1-˜40 mg/mL, ˜1.2-˜40 mg/mL, ˜1.3-40 mg/mL,˜1.4-40 mg/mL, ˜1.5-˜40 mg/mL, ˜1.6-˜40 mg/mL, ˜1.7-˜40 mg/mL, ˜1.8-˜40mg/mL, or, e.g., ˜1.9-˜40 mg/mL, as in, for example, between ˜1.1-˜38mg/mL, ˜1.2-˜36 mg/mL, ˜1.3-˜34 mg/mL, ˜1.4-˜32 mg/mL, 1.5-˜30 mg/mL,1.6-˜28 mg/mL, 1.7-˜26 mg/mL, 1.8-˜24 mg/mL, ˜1.9-˜22 mg/mL, or, e.g.,about 2.0-20 mg/mL of a suspension component. In aspects, the ionicsuspension component is hyaluronic acid.

In aspects, a suspension component comprises hyaluronic acid. Inaspects, a suspension component comprises at least mostly hyaluronicacid. In aspects, compositions provided by the invention comprise aquinolone antibiotic component and an anti-inflammatory steroidcomponent maintained in suspension, the suspension agent beinghyaluronic acid having an average molecular weight of between about200-1800 kDa, such as e.g., between ˜200-˜1750 kDa, ˜200-˜1700 kDa,˜200-˜1650 kDa, ˜200-˜1600 kDa, ˜200-˜1550 kDa, ˜200-˜1500 kDa,˜200-˜1450 kDa, ˜200-˜1400 kDa, ˜200-˜1350 kDa, ˜200-˜1300 kDa,˜200-˜1250, ˜200-1200 kDa, as in, for example, between ˜250-˜1800 kDa,˜300-˜1800 kDa, ˜350-˜1800 kDa, ˜400-˜1800 kDa, ˜450-1800 kDa, ˜500-1800kDa, ˜550-˜1800 kDa, ˜600-˜1800 kDa, ˜650-˜1800 kDa, ˜700-˜1800 kDa,˜750-˜1800 kDa, ˜800-˜1800 kDa, ˜850-˜1800 kDa, ˜900-˜1800 kDa,˜950-˜1800 kDa, ˜1000-˜1800 kDa, ˜1050-˜1800 kDa, ˜1100-˜1800 kDa,˜1150-˜1800 kDa, ˜1200-˜1800 kDa, ˜1250-˜1800 kDa, as in, for example,between ˜220-1750 kDa, ˜240-1700 kDa, ˜260-1650 kDa, ˜280-˜1600 kDa,˜300-1550 kDa, ˜320-1500 kDa, ˜340-1450 kDa, ˜340-1400 kDa, ˜340-1350kDa, ˜340-1300 kDa, ˜340-1250 kDa, or, e.g., between about 360-1200 kDa.In aspects, the average molecular weight of at least some, most,generally all, or all of the hyaluronic acid in the suspension componentis between about 360-about 1200 kDa.

In aspects, an ionic suspension component can demonstrate one or moreadditional functional activities, such as, e.g., an ionic suspensioncomponent can provide DOS lubricating activity (e.g., can DOS retainwater), DOS increase in the speed of wound healing (e.g., cornealepithelial wound healing), DOS stimulation of epithelial migration, DOSincrease the corneal contact time of composition(s), DOS increase theviscosity of composition, or any combination thereof

Non-Ionic Suspension Component

In aspects, compositions comprise a non-ionic suspension componentcomprising one or more non-ionic suspension agents (constituents). Inaspects, compositions comprise only non-ionic suspension componentconstituents. In aspects, compositions comprise non-ionic and ionicsuspension component constituents.

In aspects, a suspension component comprises, mostly comprises,generally consists of, or consists of an ophthalmologically suitablepolysorbate, such as, e.g., polysorbate-80. In aspects, a compositioncomprises a polysorbate suspension component, but the polysorbatesuspension component provides less than half of the suspension effectsof the suspension component.

In aspects, a suspension component comprises a polyoxyl-ethylated castoroil such as a Cremophor (e.g., Cremophor® EL or Cremophor® RH-40), or,e.g., non-hydroxypropylmethylcellulose cellulose derivatives such as,e.g., methyl cellulose (MC), methyl hydroxyethyl cellulose (MHEC)carboxymethylcellulose (CMC), hydroxyethyl cellulose (HEC), andhydrophobically modified HEC (HMHEC), ethyl hydroxyethyl cellulose(HEC), and hydrophobically modified cellulose ethers (HM-HEC).

While Cremophor® compositions (“compositions” as, e.g., they are oftenprovided as mixtures of compounds) is described in this section as asuspension component or suspension component constituent, in someaspects, a Cremophor® can provide DOS more activity or functionality asan, e.g., emulsifier, solubilizer, or surfactant than a suspendingagent.

In aspects, suspension components comprise a cellulose derivative whichdoes not produce a gel in aqueous solution. In aspects, the cellulosederivative is CMC. In aspects, the non-ionic suspension component doesnot comprise hydroxypropyl methylcellulose (HPMC).

In aspects, compositions comprising Cremophor® compositions arecharacterizable as suspensions, as, e.g., the presence of a Cremophor®composition such as, e.g., Cremophor® EL or Cremophor RH-40 does notprovide for all ingredients to solubilize so as to form a solution. Inaspects, the presence of a polysorbate, such as, e.g., polysorbate-80,or a Cremophor® composition, such as, e.g., Cremophor® EL or Cremophor®RH-40, DOS increases the amount that one or more actives, such as, e.g.,one or more fluoroquinolone antibiotic compounds, one or more steroidanti-inflammatory compounds, one or more non-steroid anti-inflammatorycompounds, or any combination thereof, is solubilized, however thecompositions maintain at least, e.g., ˜50%, ˜55%, ˜60%, ˜65%, ˜70%,˜75%, ˜80%, ˜85%, ˜90%, or at least 95% or more of such compound(s) insuspension. As noted elsewhere, compositions of the invention can be inany suitable form. Suspensions are one such form. Compositionsalternatively may be characterized as solutions, colloids, or emulsionsdepending on ingredients or context. In aspects, compositions aresolutions or suspensions. In aspects, compositions of the invention aresuspensions.

In some aspects, formulations described herein comprise polyoxyl ncastor oils (n=35-40) and polyoxyl hydrogenated castor oils, such as forexample polyoxyl 35 castor oil (e.g., Cremophor® EL), polyoxyl 40 castoroil (e.g., Marlowet 40, Emulgin RO 40), a polyoxyethylene hydrogenatedcastor oil (such as, e.g., polyoxyethylene hydrogenated castor oil10/polyoxyl 10 hydrogenated castor oil, polyoxyethylene hydrogenatedcastor oil 40/polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40),polyoxyethylene hydrogenated castor oil 50/polyoxyl 50 hydrogenatedcastor oil, and polyoxyethylene hydrogenated castor oil 60/polyoxyl 60hydrogenated castor oil (Cremophor® RH 60)). In aspects, one suitablepolyoxyl castor oil is polyoxyl-35-castor oil.

In certain aspects, the suspension component comprises a constituentcomposed of polyoxyl castor oil compound(s) comprising a number ofpolyoxyl groups. In one aspect, the polyoxyl castor oil compound(s) is apolyoxyl 40 hydrogenated castor oil composition. For example, in oneaspect, the polyoxyl castor oil composition is Cremophor® RH40, asuitable polyoxyl castor oil composition comprising polyoxyl castor oilcompound(s) according to the following chemical structure:

In certain aspects, suitable compounds of the suspension component usedin compositions herein can comprise compound(s) according to Formula 2,wherein x+y+z=a number other than 40, such as e.g., a number other than40 between 20-60, 30-60, 35-60, 38-60, 38-50, 38-46, 38-44, or 38-42.Also or alternatively, suitable compounds/compositions for use insuspension components herein can comprise compounds wherein x+y+z=˜39,˜38, ˜37, ˜36, ˜35, ˜34, ˜33, ˜32, ˜31, or ˜30 or even lower, or, forexample, ˜41, ˜42, ˜43, ˜44, ˜45, ˜ 46, ˜47, ˜48, ˜49, or ˜50 or evenhigher, e.g., ˜52, ˜55, or ˜58.

In other aspects, polyoxyl castor oil compositions can comprise polyoxylcastor oil compound(s) having any suitable number of polyoxyl groups,regardless of whether such polyoxyl castor oil compound(s) vary from thestructure of Formula 2 or not. In aspects, polyoxyl castor oilcompound(s) can comprise between ˜25-70, ˜25-65, ˜25-60, ˜25-55, ˜25-50,˜25-45, or ˜25-40, such as for example between ˜30-70, ˜35-70, ˜40-70,˜45-70, ˜50-70, ˜55-70, ˜60-70, or ˜65-70 polyoxyl groups, as in betweenabout 30-60, about 30-50, about 30-40, about 40-60, or between about40-50 polyoxyl groups. In certain aspects, polyoxyl castor oilcompound(s) can comprise at least 36 or more polyoxyl groups.

Accordingly, in aspects, one, some, most, generally all, essentiallyall, or all of the polyoxyl castor oil composition in ophthalmologicallysuitable compositions comprise a degree of polymerization at leastgenerally equivalent to that of Cremophor® EL (i.e., having a number ofpolyoxyl groups within about 20% of that of Cremophor® EL, within about20% of that of Cremophor® RH-40, or both, such as between about 30-45,32-42, or, e.g., between about 35-40 polyoxyl groups.)

In some respects, the polyoxyl castor oil composition comprises polyoxylcastor oil compounds which are non-hydrogenated. In certain commonaspects, the polyoxyl castor oil composition comprises hydrogenatedcastor oil compounds. In some respects, the polyoxyl castor oilcomposition mostly comprises, generally only comprises, essentiallycomprises, or comprises only hydrogenated castor oil compounds (withrespect to suspension component polyoxyl castor oil compound(s) in thecomposition).

In aspects, the ophthalmologically suitable compositions describedherein comprise a polyoxyl castor oil composition wherein at least 75%of the polyoxyl castor oil compound(s) in the polyoxyl castor oilcomposition are hydrogenated. In aspects, at least all detectable or allsuch compounds are of the polyoxyl castor oil composition arehydrogenated.

In aspects, a polyoxyl castor oil composition of the invention is apegylated/PEGylated castor oil or a hydrogenated castor oil. In aspects,such an oil can comprise a single compound or molecule or also oralternatively such an oil can be a mixture of molecules.

In aspects, the ophthalmologically suitable compositions herein comprisepolyoxyl castor oil composition(s) comprising one or more polyoxylhydrogenated castor oil compound(s) which make up 65-85% of the polyoxylhydrogenated castor oil composition.

In aspects, a polyoxyl hydrogenated castor oil composition, such as apegylated castor oil or hydrogenated castor oil, comprises or is amixture of hydrophobic and hydrophilic molecules. E.g., in somerespects, a polyoxyl castor oil composition of the compositionsdescribed herein can be a mixture of hydrophobic and hydrophilicmolecules. In aspects for example, about 70-90%, e.g., between ˜72-88%,˜74-86%, ˜76-˜84% of such a polyoxyl castor oil composition isrelatively hydrophobic. In aspects, about 75% of a polyoxyl castor oilcomposition is comprised of relatively hydrophobic molecules. Inaspects, at least ˜10%, such as at least about 15% or at least about20%, such as, e.g., between about 10-30% of a polyoxyl castor oilcomposition is relatively hydrophilic, such as, e.g., between ˜12-28,˜14-26, ˜16-24, or, e.g., ˜16-22, ˜16-20, or ˜16-18% of the polyoxylcastor oil composition mixture is comprised of relatively hydrophiliccomponents, e.g., is composed of one or more hydrophilic compounds. Inaspects, about 25% of the polyoxyl castor oil composition mixture iscomprised of relatively hydrophilic components.

In aspects, components of a polyoxyl castor oil composition's relativelyhydrophobic portion can comprise or even be mostly comprised of any oneor more hydrophobic molecules known in the art to be suitably present intypes of such compositions suitable for pharmaceutical uses, includingbut not limited to glycerol polyethylene glycol ricinoleate,polyethylene glycol 12-oxystearate, glycerol polyethylene glycolhydroxy-stearate, or mixtures thereof. In aspects, such molecules arepresent together with fatty acid glycerol polyglycol esters to form ahydrophobic part of the polyoxyl castor oil composition.

In aspects, components of a polyoxyl castor oil composition's relativelyhydrophilic portion can comprise or even be mostly comprised of any oneor more hydrophilic molecules known in the art to be present in suchcompositions, including but not limited to polyethylene glycols,glycerol ethoxylates, and mixtures thereof. In certain embodiments,compositions herein comprise polyoxyl castor oil compositions whereinsome, most, essentially all, or all, such as, e.g., at least about 10%,at least ˜20%, at least ˜30%, at least ˜40%, at least ˜50%, at least˜60%, at least ˜70% or even more, e.g., at least ˜15-35% of the polyoxylcastor oil composition is composed of one or more hydrophilic compounds,such as, e.g., is at least mostly composed of polyethylene glycol,glycerol ethoxylates, or a mixture thereof.

In aspects, a class of castor oils particularly suitable for thecompositions herein are referred to as “Cremophors” (because many suchproducts are commercially available previously under the trademarksCREMOPHOR® or currently KOLLIPHOR® (and sold by BASF Corp.). In aspects,such compositions are synthesized by reacting either castor oil orhydrogenated castor oil with varying amounts of ethylene oxide.

In some respects, ophthalmologically suitable compositions describedherein can comprise one or more fluoroquinolone antibiotic compounds,one or more steroid anti-inflammatory compounds, one or more non-steroidanti-inflammatory compounds, or a combination thereof, and a polyoxylcastor oil composition comprising hydrogenated compounds, such as, e.g.,the polyoxyl castor oil composition can be or can comprise a polyoxylhydrogenated castor oil. Polyoxyl hydrogenated castor oils suitable forthe invention herein can comprise but may not be limited to, e.g.,polyoxyl 35 castor oil (e.g., Cremophor® EL), polyoxyl 40 castor oil(e.g., Marlowet 40, Emulgin RO 40), a polyoxyethylene hydrogenatedcastor oil (such as, e.g., polyoxyethylene hydrogenated castor oil10/polyoxyl 10 hydrogenated castor oil, polyoxyethylene hydrogenatedcastor oil 40/polyoxyl 40 hydrogenated castor oil (Cremophor® RH40/Kolliphor RH40), polyoxyethylene hydrogenated castor oil 50/polyoxyl50 hydrogenated castor oil, and polyoxyethylene hydrogenated castor oil60/polyoxyl 60 hydrogenated castor oil (Cremophor® RH 60)). Othersuitable polyoxyl castor oil compositions can comprise but may not belimited to Solutol HS 15 or other similar compositions having similar orequivalent properties (e.g., having properties such as HLB, criticalmicelle concentration, etc.) In aspects, such compositions can furthercomprise one or more pharmaceutically acceptable excipients. In aspects,such compositions remain stable when stored at room temperatureconditions and/or accelerated conditions.

In some aspects, the polyoxyl castor oil composition compounds of theophthalmologically suitable compositions of the invention can have acritical micelle concentration that lies between about 0.005 and about0.04% (at about 37 degrees Celsius), such as, e.g., between ˜0.008-0.04%or between ˜0.009-0.04, such as between ˜0.01-0.04%, such as between˜0.012 and ˜0.038%, between ˜0.014 and ˜0.036%, between ˜0.016 and˜0.034%, between ˜0.018 and ˜0.032%, or, e.g., can have a criticalmicelle concentration of between about 0.02 and about 0.03%. In somerespects, the polyoxyl castor oil composition compound(s) has a criticalmicelle concentration of about 0.03% at 37 degrees Celsius. In certainaspects, the polyoxyl castor oil composition has a critical micelleconcentration higher than 0.02%. In certain aspects, the polyoxyl castoroil composition has a critical micelle concentration higher than that ofCremophor® EL.

In aspects, the polyoxyl castor oil composition component in thecomposition produces emulsions with particle sizes that are detectablyor significantly larger than those produced by emulsions emulsified byCremophor® EL. In aspects, the polyoxyl castor oil composition componentin the composition produces emulsions with particle sizes in adetectably or significantly larger range of particles than the range ofparticle sizes in an emulsion emulsified by Cremophor® EL.

In aspects, the average droplet size formed by a polyoxyl castor oilcomposition when in an emulsion formulation is between about 60 andabout 80 nanometers (nm), such as, e.g., between ˜62-80, ˜64-80, ˜66-80,˜68-80, or between ˜70-80 nm, such as for example between ˜60-78,˜60-76, ˜60-74, ˜60-72, ˜60-70, or between about ˜60-68 nm. In certainaspects, the average droplet size formed by a polyoxyl castor oilcomposition is between ˜65 and ˜68 nm. In certain aspects, the averagedroplet size formed by a polyoxyl castor oil composition is less than 70nm, such as less than about 69 nm, or less than ˜68 nm.

In certain aspects, suitable polyoxyl castor oil compositions of theinvention or suitable polyoxyl castor oil compound(s) in polyoxyl castoroil compositions are characterizable by their packing parameter. Packingparameter is a characteristic defined by the formula “v/al”, wherein “v”is the hydrophobic volume, “a” is the hydrophilic area, and “1” is thehydrophobic chain length. In aspects, some, most, generally all, or allpolyoxyl castor oil compositions used in compositions of the inventionhave a packing parameter of within about 20% of that of Cremophor® EL,within about 20% of that of Cremophor® RH-40, or both.

In aspects, the polyoxyl castor oil composition or some, most, generallyall, or all polyoxyl castor oil compounds of a polyoxyl castor oilcomposition has a polydispersity index (PDI) of between about 0.1 andabout 0.2, such as, e.g., between ˜0.1 and ˜0.19, between ˜0.1 and˜0.18, between ˜0.1 and ˜0.17, between ˜0.1 and ˜0.16, or, e.g., between˜0.1 and ˜0.15, such as for example between ˜0.15 and ˜0.2, or between0.15 and ˜0.19. In aspects, a polyoxyl castor oil composition of theophthalmologically suitable compositions of the invention or thepolyoxyl castor oil compounds of the polyoxyl castor oil composition ofa composition have a PDI of between about 0.15 and about 0.16. Incertain aspects, some, most, generally all, essentially all, or allpolyoxyl castor oil compounds of the polyoxyl castor oil composition ofan ophthalmologically suitable composition herein have or the polyoxylcastor oil composition of a composition has a PDI of less than 0.17.

In aspects, the polyoxyl castor oil composition in the compositionsdescribed herein has a hydrophilic-lipophilic balance (HLB) that liesbetween ˜11 and ˜17, such as, e.g., between ˜12 and ˜17, such as between˜13 and ˜17 or between ˜14 and ˜17, such as, e.g., between ˜12 and ˜16,between ˜12 and ˜15, between ˜12 and ˜14, or between ˜13 and ˜16, or,e.g., between ˜14 to ˜16.

In aspects, the average molecular weight of some, most, ≥˜75%, ≥˜90%, or≥˜95% of the polyoxyl castor oil compound(s) in the polyoxyl castor oilcomponent of the composition is/are greater than about 1700 g/mol-1,such as greater than about 1800 g/mol-1, greater than about 1900g/mol-1, or greater than about 2000 g/mol-1, such as, e.g., greater than˜2050 g/mol-1, greater than ˜2100 g/mol-1, greater than ˜2150 g/mol-1,greater than ˜2200 g/mol-1, greater than ˜2250 g/mol-1, greater than ˜2300 g/mol-1, greater than ˜2350 g/mol-1, greater than ˜2400 g/mol-1,greater than ˜2450 g/mol-1, greater than about 2500 g/mol-1, or evenhigher. In aspects, the average molecular weight of the polyoxyl castoroil compound(s) in the polyoxyl castor oil composition component of theophthalmologically suitable compositions is at least about 15%, such asat least ˜16%, at least ˜17%, at least ˜18%, at least ˜19%, or at least˜20% greater than the average molecular weight of the polyoxyl castoroil compounds of Cremophor® EL, Cremophor® RH-40, or both.

In certain aspects, the polyoxyl castor oil composition of thecompositions herein comprises an amount/degree of ethoxylation withinabout 20% of that of Cremophor® EL, within about 20% of that ofCremophor® RH-40, or both.

In certain aspects, a polyoxyl castor oil composition of thecompositions herein can DOS improve the solubility of one or morecomponents of the compositions. In aspects, the solubility of the activepharmaceutical ingredient in the compositions of the invention, e.g., afluoroquinolone antibiotic compound, a steroid anti-inflammatorycompound, a non-steroid anti-inflammatory compound, or both is at leastabout 0.5%, ˜1%, ˜2%, ˜3%, ˜4%, or at least about 5% or more higher inthe composition comprising the polyoxyl castor oil composition than in acomposition lacking the polyoxyl castor oil composition.

In certain aspects, a polyoxyl castor oil composition of thecompositions herein can DOS improve upon the permeability,bioavailability, or both, of one or more active pharmaceuticalingredients of the composition, e.g., can improve upon the permeability,bioavailability, or both of a fluroquinolone antibiotic compound, asteroid anti-inflammatory compound, a non-steroid anti-inflammatorycompound, or combination of any or all thereof. In aspects, thepermeability (e.g., of optical tissue) of at least one of afluroquinolone antibiotic compound, a steroid anti-inflammatorycompound, or a non-steroid anti-inflammatory compound in thecompositions of the invention is at least about 0.5%, ˜1%, ˜2%, ˜3%,˜4%, or at least about 5% or more higher in the composition comprisingthe polyoxyl castor oil composition than in a composition lacking thepolyoxyl castor oil composition. In aspects, the bioavailability of afluroquinolone antibiotic compound, a steroid anti-inflammatorycompound, a non-steroid anti-inflammatory compound, or combination ofany or all thereof in the compositions of the invention is at leastabout 0.5%, ˜1%, ˜2%, ˜3%, ˜4%, or at least about 5% or more higher inthe composition comprising the polyoxyl castor oil composition than in acorresponding composition lacking the polyoxyl castor oil composition.

In aspects, ophthalmologically suitable compositions of the inventioncomprising a polyoxyl castor oil composition are capable of retaining aDOS higher amount (content) of one or more fluroquinolone antibioticcompound(s), a steroid anti-inflammatory compound(s), or non-steroidanti-inflammatory compound(s) in suspension when the composition isstored at about 22° C.-about 25° C. and about 40% relative humidity, or,e.g., at about 40° C. and not more than 25% relative humidity, or both(ophthalmic product), or, e.g., 25° C. and 60% relative humidity or at40° C. and 75% relative humidity for 3 months (injectable product), fora period of at least about 3 months.

In some respects, the polyoxyl castor oil composition of an inventivecomposition herein does not impart DOS biological effects in therecipient of the composition. According to aspects, the polyoxyl castoroil composition of a composition is inert. In aspects, the polyoxylcastor oil composition or compound therein present in anophthalmologically suitable composition herein does not impart an effecthaving a direct clinical implication; that is, in aspects, theophthalmologically suitable compositions described herein impartclinical effects related to the one or more fluroquinolone antibioticcompound(s), a steroid anti-inflammatory compound(s), or non-steroidanti-inflammatory compound(s) whereby no additional statisticallysignificant clinical effect is imparted by a polyoxyl castor oilcomposition of the composition.

In certain aspects, the polyoxyl castor oil compositions inophthalmologically suitable compositions of the invention arecharacterizable as non-foaming; e.g., in aspects, suitable polyoxylcastor oil compositions of the composition described herein arecharacterizable as showing little tendency to form a foam (no detectablefoaming or significant amount of foam formation) or are otherwise knownin the art not to be likely to form a foam.

In one aspect, a polyoxyl castor oil composition of the compositionsherein does not DOS cause severe anaphylactoid hypersensitivityreactions, hyperlipidemia, abnormal lipoprotein patterns, aggregation oferythrocytes, peripheral neuropathy, or any combination thereof.

In one aspect, a polyoxyl castor oil composition does not cause a DOStoxic response/reaction to the composition comprising the polyoxylcastor oil composition.

In a specific aspect, a suitable polyoxyl castor oil composition of theophthalmic compositions herein is a polyoxyl 35 castor oil formulation,also known as Cremophor® ® EL (BASF, Inc., Ludwigshafen, Germany) orEtocas 35 (Croda, Inc., Parsippany, N.J., USA). In certain alternativeaspects, the polyoxyl castor oil composition is not polyoxyl 35 castoroil (e.g., is not Cremophor® EL).

In another specific aspect, a suitable polyoxyl castor oil compositionof the composition is an emulsifying agent obtained by reactinghydrogenated castor oil with ethylene oxide. In aspects, such a polyoxylcastor oil composition is a PEG-40 hydrogenated castor oil, e.g.,Cremophor® RH40 (also known as Kolliphor® RH40).

In aspects, the polyoxyl castor oil compositions suitable for thecompositions herein (e.g., Cremophor® RH40) can be characterizable assoft or flowing pastes at 23 degrees Celsius (° C.). In aspects,suitable polyoxyl castor oil compositions have a very faint or no DOSodor. In aspects, suitable polyoxyl castor oil compositions can formclear solutions in water, are capable of forming clear solutions inethanol, can form clear solutions in isopropanol, or any combinationthereof. In some respects, suitable polyoxyl castor oil compositions canform clear mixtures with fatty acids. In some respects, suitablepolyoxyl castor oil compositions can form clear mixtures with fattyalcohols.

In one aspect, suitable polyoxyl castor oil compositions have asulphated ash content of ≤0.5 g/100 g, such as, e.g., ≤0.4 g/100 g or≤0.3 g/100 g, such as, e.g., ≤0.29 g/100 g, ≤0.28 g/100 g, ≤0.27 g/100g, ≤0.26 g/100 g, ≤0.25 g/100 g, ≤0.24 g/100 g, ≤0.23 g/100 g, ≤0.22g/100 g, ≤0.21 g/100 g, ≤0.20 g/100 g, or even less.

In aspects, suitable polyoxyl castor oil compositions of thecompositions herein can have an iodine value of ≤about 2.0/100 g, suchas, e.g., ≤about 1.8/100 g, ≤about 1.6/100 g, ≤about 1.4/100 g, ≤about1.2/100 g, or ≤about 1.0/100 g or even less, such as ≤about 0.8/100 g,≤0.6/100 g, ≤about 0.4/100 g or even less.

In aspects, suitable polyoxyl castor oil compositions of thecompositions herein can have a saponification value of between about 30and about 80 mg KOH/g, such as, e.g., between ˜35-75 mg KOH/g, between˜40-70 mg KOH/g, ˜45-65 mg KOH/g, or, e.g., between about 50-60 mgKOH/g.

In aspects, the polyoxyl castor oil compositions detectably orsignificantly enhance the penetration of fluoroquinolone antibioticcompound(s), steroid anti-inflammatory compound(s), non-steroidanti-inflammatory compounds, or any combination thereof, in eye tissueof subject(s).

In certain aspects, suitable polyoxyl castor oil compositions can have ahydroxyl value of between about 40 and about 95 mg KOH/g, such as, e.g.,between ˜45-90 mg KOH/g, between ˜50-85 mg KOH/g, between ˜ 55-80 mgKOH/g, or, for example, between ˜60-75 mg KOH/g.

In certain aspects, suitable polyoxyl castor oil compositions cancomprise an amount of 1,4-dioxane which is less than or equal to about20 mg/Kg, such as ≤about 18 mg/Kg, ≤about 16 mg/Kg, ≤about 14 mg/Kg,≤about 12 mg/Kg, ≤about 10 mg/Kg, or even less, such as ≤about 8 mg/Kg,≤about 6 mg/Kg, ≤about 4 mg/Kg, or ≤about 2 mg/Kg.

In certain aspects, suitable polyoxyl castor oil compositions herein cancomprise an acid value of less than or equal to about 2.0 mg KOH/g, suchas ≤about 1.8 mg KOH/g, ≤about 1.6 mg KOH/g, ≤1.4 mg KOH/g, ≤about 1.2mg KOH/g, ≤about 1.0 mg/KOH/g, or even less.

In certain aspects, suitable polyoxyl castor oil compositions of thecompositions herein can have a pH of between about 5.5-6.6, such as,e.g., between about 5.6-6.4, ˜5.7-6.3, ˜5.8-6.2, ˜5.9-6.1, or between,e.g., ˜5-6.

In aspects, suitable polyoxyl castor oil compositions of thecompositions described herein can have a water content value (asdetermined by a Karl Fischer titration method) of, e.g., less than orequal to about 3.0 g/100 g, such as ≤about 2.8 g/100 g, ≤about 2.6 g/100g, ≤about 2.4 g/100 g, ≤about 2.2 g/100 g, ≤about 2.0 g/100 g, or evenless, such as ≤about 1.8 g/100 g or ≤about 1.6 g/100 g or even less.

In aspects, the heavy metal content of suitable polyoxyl castor oilcompositions of the invention is less than or equal to about 20 ppm,such as S about 18 ppm, ≤about 16 ppm, ≤about 14 ppm, ≤about 12 ppm, or≤about 10 ppm or less, such as ≤about 8 ppm or ≤about 6 ppm or less.

In aspects, the non-ionic suspension agent is polysorbate, e.g.,polysorbate-80. In aspects, the non-ionic suspension agent is apolyoxyl-ethylated castor oil, such as, e.g., Cremophor® EL. In aspects,the non-ionic suspension agent is a polyoxyl-ethylated castor oil, suchas, e.g., Cremophor® RH-40.

In aspects, the composition comprises a non-ionic surfactant in anamount of between about 1-20 mg/mL, such as between ˜2-˜20 mg/mL, ˜2-˜18mg/mL, ˜2-˜16 mg/mL, ˜2-˜14 mg/mL, ˜2-˜12 mg/mL, or, e.g., ˜2-˜10 mg/mL,such as, e.g., between ˜4-˜20 mg/mL, ˜6-˜20 mg/mL, ˜8-˜20 mg/mL, ˜10-˜20mg/mL, as in, e.g., between ˜2-˜18 mg/mL, ˜4-˜16 mg/mL, ˜6-˜14 mg/mL,˜8-˜12 mg/mL, ˜9-˜11 mg/mL, or, e.g., about 10 mg/mL. In aspects, thenon-ionic surfactant is polysorbate-80, Cremophor® EL, Cremophor® RH-40.

In aspects, a non-ionic suspension component is also a surfactant, e.g.,exhibits DOS surfactant (surface-active) activity. In aspects, thenon-ionic suspension component is also a non-ionic surfactant. Inaspects, the non-ionic suspension and surfactant is, e.g.,polysorbate-80, Cremophor® EL, Cremophor® RH-40, or a combinationthereof. In specific aspects, the non-ionic suspension and surfactant ispolysorbate-80. In aspects a non-ionic suspension and surfactant is aPEG 3350.

Natural/Semi-Synthetic Suspension Component

In aspects, suspension components of the compositions comprise aneffective amount of a suspension component which is at least generallyall, substantially all, or is/are natural or semi-synthetic suspensionagent(s). In aspects, the natural or semi-synthetic suspension agent canbe any ophthalmologically suitable natural or semi-natural suspensionagent. In aspects, the natural or semi-synthetic suspension agent is notxanthan gum.

In aspects, the suspension component comprises one or more constituentcompounds wherein ocular epithelial cells have receptors for thecompound. In aspects, for example, the suspension component can comprisehyaluronic acid, and hyaluronic acid can, in aspects, DOS bind to HAREreceptors on the surface of ocular epithelial cells. In aspects, thepresence of a naturally occurring receptor on the surface of ocularepithelial cells for a constituent compound of a suspension componentincreases the amount of suspension component endocytosed by such cells,the rate of uptake by such cells of the suspension component, or both,such that the suspension component demonstrates a DOS rate of ocularwound healing when compositions are providing under circumstances whereocular wound(s) are present, such as, e.g., when compositions herein areprovided in association with an invasive ophthalmic procedure.

In aspects, suspension component(s) of compositions herein comprise atleast one ingredient, such as, e.g., at least 2, at least 3, or at leastabout 4 ingredients which are naturally occurring compounds found in theeye, such as, e.g., compounds naturally found in, e.g., the vitreoushumor aqueous humor). In aspects, suspension component(s) comprisehyaluronic acid. In aspects, compositions comprise 2 or more compoundswhich are naturally occurring compounds found in the eye. In aspects,compositions comprise, e.g., hyaluronic acid and chondroitin sulfate.

In aspects, one or more suspension components is a natural orsemi-synthetic (e.g., semi-natural) suspension agent characterizable ashaving DOS, such as significant, hygroscopic properties. In aspects, asuspension agent is a natural or semi-synthetic/semi-natural suspensionagent having a DOS greater hygroscopicity than that ofhydroxypropylmethylcellulose (HPMC), than that of a non-ionicpolyoxyethylene-polyoxypropylene block polymer having the chemicalstructure—HO—(CH2-CH2-O)x (C3H6-O)y-(CH2-CH2-O)x-H, wherein x is aninteger having the value of at least 8 and y is an integer having thevalue of at least 38, that of xanthan gum, or any combination thereof.In aspect, the suspension agent is a natural orsemi-synthetic/semi-natural suspension agent having a hygroscopicitywherein the agent has the ability to absorb a DOS higher amount of waterper its mass than that of HPMC, than that of a non-ionicpolyoxyethylene-polyoxypropylene block polymer having the chemicalstructure—HO—(CH2-CH2-O)x (C3H6-O)y-(CH2-CH2-O)x-H, wherein x is aninteger having the value of at least 8 and y is an integer having thevalue of at least 38, that of xanthan gum, or any combination thereof.In aspects, a suspension agent is a natural or semi-synthetic suspensionagent having a DOS faster rate of water absorption than that ofhydroxypropylmethylcellulose (HPMC), than that of a non-ionicpolyoxyethylene-polyoxypropylene block polymer having the chemicalstructure—HO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein x is aninteger having the value of at least 8 and y is an integer having thevalue of at least 38, that of xanthan gum, or any combination thereof.

In aspects, the suspension component can comprise at least one naturalor semi-synthetic suspension agent composed of a compound having anaverage molecular weight of between about 10,000 and about 1,500,000Daltons (10 kDa-1500 kDa), such as, e.g., between about 100 kDa-about1400 kDa, ˜200 kDa-˜1300 kDa, or, e.g., between about 300 kDa-˜1200 kDa,such as, e.g., between ˜360 kDa-˜1200 kDa. In aspects, a natural orsemi-synthetic suspension agent is mostly all, generally all, or allhyaluronic acid.

Other Ingredients & APIs

In aspects, compositions of the invention comprise, in addition to thequinolone antibiotic API(s), anti-inflammatory API(s), or both, andother primary ingredients (e.g., suspension agent(s) of a suspensioncomponent), one or more additional API(s), additional excipients, orboth.

In aspects, an excipient is one or more of a bulking agent, filler,solubilizer, absorption enhancer, chelating agent, antioxidant, tonicityagent, pH-adjusting agent, preservative, thickening agent/viscosityenhancer, carrier, diluent, etc. In aspects, such excipients aresuitable for ophthalmological use and present in amounts safe forophthalmic administration. A pharmaceutically acceptable ingredient canin aspects, be a pharmaceutically acceptable active ingredient which isan ingredient compatible with other ingredient(s) of the composition andnot deleterious to the recipient thereof.

In aspects, compositions comprise one or more antifungal (e.g.,antimycotic) compounds (constituents/APIs), including, e.g., one or moresynthetic antifungal compounds (constituents), classifiable as, e.g.,polyenes, azoles, allylamines, and echinocandins, or antiviral compounds(constituents), classifiable as, e.g., attachment or fusion inhibitors,entry inhibitors, uncoating inhibitors, protease inhibitors, polymeraseinhibitors, nucleoside and nucleotide reverse transcriptase inhibitors(including nucleoside analogue reverse transcriptase inhibitors(NRTIs)), nonnucleoside reverse-transcriptase inhibitors, and integraseinhibitors, including antiviral compounds which can be described as(which may or may not fit into a previously described group) chemokinecoreceptor antagonists. In aspects, in addition to the describedquinolone antibiotic API(s) of the composition the composition comprisesone or more other antibacterial/antibiotic API(s), such as, e.g., one ormore aminoglycosides, carbapenems, cephalosporins, fluoroquinolones,glycopeptides and lipoglycopeptides, macrolides, monobactams,oxazolidones, penicillins, polypeptides, rifamycins, sulfonamides,streptogramins, and tetracyclines. In certain aspects, carbapenems,cephalosporins, monobactams, and penicillins can be grouped together asbeta-lactam antibiotics. In aspects, compositions comprise antibioticcompounds which may not fall neatly into one of the above-referencedclasses, such as, e.g., chloramphenicol, clindamycin, daptomycin,Fosfomycin, Lefamulin, metronidazole, mupirocin, nitrofurantoin,tigecycline, etc. In aspects, compositions comprise one or morenon-quinolone broad-spectrum antibiotics such as, e.g., doxycycline,minocycline, aminoglycosides (except for, e.g., streptomycin),ampicillin, amoxicillin/clavulanic acid, azithromycin, carbapenems,piperacillin/tazobactam, quinolones, tetracycline-class drugs (except,e.g., sarecycline), chloramphenicol, ticarcillin,trimethoprim/sulfamethoxazole, etc. In aspects, compositions compriseAPI(s) for the treatment of other conditions. In certain aspects,composition(s) do not comprise any API(s) other than any indicatedquinolone antibiotic API(s), anti-inflammatory API(s), or both.

Compositions of the invention can, and often will, comprise additionalexcipients besides the above-described suspension agent and surfactantcomponents of certain compositions.

In aspects, one or more additional excipients is any one or more of atonicity agent, a preservative, a surfactant, a buffer/buffering agent,a viscoelasticity agent, a vehicle, a chelating agent, an emulsifier, asequestration agent, a penetration enhancer, a pH adjusting agent, anantioxidant, etc. In general, compositions can include any suitableexcipient(s). In aspects, compositions are characterized by inclusion ofcertain excipients (e.g., a chelating agent, which can be considered aprimary ingredient in aspects). A description of select classes ofexcipients that can be included in compositions of the inventionfollows.

Chelating Agent(s)

In aspects, compositions provided by the invention comprise one or moreophthalmologically suitable chelating agents. In alternative aspects,compositions provided by the invention do not comprise a chelatingagent. In aspects, one or more chelating agents DOS stabilize one ormore active ingredients, such as one or more antimicrobial agents (e.g.,a fluoroquinolone antibiotic compound), one or more anti-inflammatorycompounds (e.g., a steroid or non-steroid anti-inflammatory compound),or both, such as, e.g., by DOS preventing flocculation, DOS preventingpremature development of DOS impurities, and the like.

According to aspects, chelating agent(s) are present in composition(s)of the invention which detectably or significantly enhance stability,detectably or significantly enhance preservative effectiveness, or,e.g., detectably or significantly reduce the amount of impurities, suchas providing for a composition which is stable under room temperaturestorage conditions, e.g., retains at least ˜90% of the one or moreantimicrobial compound constituents and at least ˜90% of the one or moreanti-inflammatory compound constituents when stored at ordinary/standardstorage conditions of about 25° C.+/−2° C. and about 40% relativehumidity, at about 40° C. and not more than 25% relative humidity, orboth (ophthalmic product), or, e.g., 25° C. and 60% relative humidity orat 40° C. and 75% relative humidity for 3 months (injectable product),for at least about one month such as ≥˜2 months or such as ≥˜3 months,≥˜4 months, ≥˜5 months, or, e.g., ≥˜6 months.

For example, composition(s) provided by the invention can comprisechelating agent(s) which detectably improve the stability of the one ormore quinolone antibiotic component constituents, or one or moreanti-inflammatory steroid component constituents, provide a reducedamount of total impurities over that provided by the same compositionlacking a chelating agent, enhance preservative effectiveness, or any orall thereof, at a period of at least 2 weeks post manufacturing, such asat a period ≥˜3 weeks, ≥˜1 month, ≥˜6 weeks, ≥˜22 months, ≥˜10 weeks,≥˜3 months, ≥˜14 weeks, ≥˜4 months, ≥˜18 weeks, ≥˜5 months, ≥˜22 weeks,≥˜6 months, or more (e.g., 3-36 months, 2-24 months, 3-24 months, 4-24months, 4-36 months, 6-24 months, 6-36 months, 12-36 months, 18-36months, 18-24 months, 12-60 months, 12-48 months, or ≥12, ≥18, ≥24, ≥30,or ≥36 months).

In aspects, the invention provides composition(s) comprising one or moreophthalmologically suitable chelating agents capable of sequesteringdivalent or polyvalent metal cations, effective at pH range of between,e.g., ˜5.5-˜9.5, such as between ˜6.0-˜9.0, e.g., or, e.g., ˜6.5-˜8.5.In aspects, a chelating agent of the composition(s) herein do notdetectably or significantly negatively impact any other component of theformulation, such as, e.g., they do not detectably or significantlyreduce the efficacy of any one or more quinolone antibiotic componentconstituents, anti-inflammatory steroid component constituents (e.g.,reduce microbial growth inhibitory effect or anti-inflammatory effect),or any other API or excipient present or which may be present in thecomposition.

In aspects any ophthalmologically suitable and pharmaceuticallyacceptable chelating agent is used. In aspects, exemplary chelatingagents present in a composition described herein comprise, e.g., sodiumcitrate, cromolyn, monomeric polyacids such as an EDTA compound,cyclohexanediamine tetraacetic acid (CDTA),hydroxyethylethylenediaminetriacetic acid (HEDTA),diethylenetriaminepentaacetic acid (DTPA), dimercaptopropane sulfonicacid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ATP A); suitable and effective derivatives or analogsof any thereof, or other related compounds (as exemplified with respectto other variant compounds described above in connection with APIs) (orequivalents thereof); any ophthalmologically acceptable salts thereof,and/or combinations of any two or more such compounds. In other aspects,a chelating agent is a phosphate, such as, e.g., pyrophosphates,tripolyphosphates, and, hexametaphosphates; a chelating antibiotic suchas chloroquine and tetracycline; a nitrogen-containing chelating agentcontaining two or more chelating nitrogen atoms within an imino group orin an aromatic ring (e.g., diimines, 2,2′-bipyridines, etc.); or forexample a polyamine such as cyclam (1,4,7,11-tetraazacyclotetradecane),N—(C₁-C₃₀ alkyl)-substituted cyclams (e.g., hexadecyclam, tetramethylhexadecyl cyclam), diethylenetriamine (DETA), spermine,diethylnorspermine (DENSPM), diethylhomospermine (DEHOP), anddeferoxamine (N′-[5-[[4-[[5-(acetylhydroxyamino) pentyl]amino]-1,4-dioxobutyl]hydroxy-amino]pentyl]-N′-(5-aminopentyl)-N-hydroxybutanediamide;also known as desferrioxamine B and DFO).

In aspects, composition(s) provided by the invention comprise ≥1ophthalmologically suitable chelating agents characterizable as amonomeric polyacid. In aspects, a chelating agent comprises anethylenediaminetetraacetic acid (EDTA) compound or an ophthalmologicallysuitable EDTA salt such as, e.g., diammonium EDTA, disodium EDTA,dipotassium EDTA, triammonium EDTA, trisodium EDTA, tripotassium EDTA,or disodium edetate/edetate disodium, or also known as edetate calciumdisodium. In aspects, compositions comprise a chelating agent thatresults in a significantly similar (e.g., statistically similar) ormeasurably improved stability of the active ingredients as compared todisodium edetate. In this sense, compositions also can be described ascomprising a “means” for chelation. In such a respect, any knownequivalents of such named agents can also be, e.g., are, incorporatedinto compositions or methods of the invention.

In aspects, one or more chelating agents such as disodium edetate ispresent in the compositions provided by the invention in an amountrepresenting between about 0.01 mg/mL-about 2 mg/mL, such as e.g.,between ˜0.01-˜1.9 mg/mL, ˜0.01-˜1.8 mg/mL, ˜0.01-˜1.7 mg/mL, ˜0.01-˜1.6mg/mL, ˜0.01-˜1.5 mg/mL, ˜0.01-˜1.4 mg/mL, ˜0.01-˜1.3 mg/mL, ˜0.01-˜1.2mg/mL, ˜0.01-˜1.1 mg/mL, ˜0.01-˜1 mg/mL, ˜0.01˜ 0.9 mg/mL, ˜0.01-˜0.8mg/mL, ˜0.1-˜0.7 mg/mL, ˜0.01-˜0.6 mg/mL, ˜0.01-˜0.5 mg/mL, as in, forexample, between ˜0.02-˜2 mg/mL, ˜0.03-˜2 mg/mL, ˜0.04-˜2 mg/mL,˜0.05-˜2 mg/mL, ˜0.06-˜2 mg/mL, ˜0.07-˜2 mg/mL, ˜0.08-˜2 mg/mL, ˜0.09-˜2mg/mL, ˜0.1-˜2 mg/mL, as in, for example, between ˜0.02-˜1.9 mg/mL,˜0.03-˜1.8 mg/mL, ˜0.04-˜1.7 mg/mL, ˜0.05-˜1.6, g/mL, ˜0.06-˜1.5 mg/mL,˜0.07-˜1.4 mg/mL, ˜0.08-˜1.3 mg/mL, ˜0.09-1.2 mg/mL, ˜0.1-˜1.1 mg/mL,˜0.1-˜1 mg/mL, ˜0.1-˜0.9 mg/mL, ˜0.1-˜0.8 mg/mL, ˜0.1-˜0.7 mg/mL,˜0.1-˜0.6 mg/mL, or, e.g., about 0.1-about 0.5 mg/mL. In aspects, thechelating agent is disodium edetate.

In aspects, composition(s) provided by the invention comprise ≥1pharmaceutically acceptable chelating agents which result in asignificantly similar or improved stability of the active ingredients ascompared to disodium edetate in a concentration of about 0.1-about 0.5mg/mL. In aspects, composition(s) provided by the invention comprise ≥1pharmaceutically acceptable chelating agents which result in asignificantly similar or improved stability of the active ingredients ascompared to disodium edetate in a concentration of between about 0.01mg/mL-about 2 mg/mL, such as e.g., between ˜0.01-˜1.9 mg/mL, ˜0.01-˜1.8mg/mL, ˜0.01-˜1.7 mg/mL, ˜0.01-˜1.6 mg/mL, ˜0.01-˜1.5 mg/mL, ˜0.01-˜1.4mg/mL, ˜0.01-˜1.3 mg/mL, ˜0.01-˜1.2 mg/mL, ˜0.01-˜1.1 mg/mL, ˜0.01-˜1mg/mL, ˜0.01˜ 0.9 mg/mL, ˜0.01-˜0.8 mg/mL, ˜0.1-˜0.7 mg/mL, ˜0.01-˜0.6mg/mL, ˜0.01-˜0.5 mg/mL, as in, for example, between ˜0.02-˜2 mg/mL,˜0.03-˜2 mg/mL, ˜0.04-˜2 mg/mL, ˜0.05-˜2 mg/mL, ˜0.06-˜2 mg/mL, ˜0.07-˜2mg/mL, ˜0.08-˜2 mg/mL, ˜0.09-˜2 mg/mL, ˜0.1-˜2 mg/mL, as in, forexample, between ˜0.02-˜1.9 mg/mL, ˜0.03-˜1.8 mg/mL, ˜0.04-˜1.7 mg/mL,˜0.05-˜1.6, g/mL, ˜0.06-˜1.5 mg/mL, ˜0.07-˜1.4 mg/mL, ˜0.08-˜1.3 mg/mL,˜0.09-˜1.2 mg/mL, ˜0.1-˜1.1 mg/mL, ˜0.1-˜1 mg/mL, ˜0.1-˜0.9 mg/mL,˜0.1-˜0.8 mg/mL, ˜0.1-˜0.7 mg/mL, ˜0.1-˜0.6 mg/mL, or, e.g., about0.1-about 0.5 mg/mL.

In aspects, compositions comprise between about 0.1-15 mg/mL of achelating agent such as sodium citrate, e.g., in an amount between˜0.1-14.5 mg/mL, ˜0.1-14 mg/mL, ˜0.1-˜13.5 mg/mL, ˜0.1-˜13 mg/mL,˜0.1-˜12.5 mg/mL, ˜0.1-˜12 mg/mL, ˜0.1-˜11.5 mg/mL, ˜0.1-˜11 mg/mL,˜0.1-˜10.5 mg/mL, or, e.g., ˜0.1-˜10 mg/mL, such as, e.g., ˜0.2-˜15mg/mL, ˜0.3-˜15 mg/mL, ˜0.4-˜15 mg/mL, ˜0.5-˜15 mg/mL, ˜0.6-˜15 mg/mL,˜0.7-15 mg/mL, ˜0.8-15 mg/mL, ˜0.9-15 mg/mL, ˜1-15 mg/mL, such as, e.g.,between ˜0.2-14 mg/mL, ˜0.4-13 mg/mL, ˜0.6-12 mg/mL, ˜0.8-11 mg/mL, or,e.g., between about 1-about 10 mg/mL of a chelating agent such as, e.g.,sodium citrate.

Preservative(s)

In aspects, compositions provided by the invention comprise one or moreophthalmologically suitable preservation agent(s) (“preservatives”). Inalternative aspects, compositions provided by the invention do notcomprise a preservative, such that the composition(s) provided by theinvention are characterizable as “preservative free.” In aspects,compositions lack any significant amount of any agent that issolely/mostly characterizable as a preservative or that is at allcharacterized as a preservative.

Uncontradicted, any aspect described herein as being “free” of acomponent/element simultaneously implicitly provides such “low” amountcompositions of the ingredient/component in question (a low amountmeaning less than 5%, less than 2%, less than 1%, less than 0.5%, lessthan 0.2%, less than 0.1%, less than 0.05%, less than 0.02%, or lessthan 0.01% of the composition on a weight basis, volume basis, orcompound number basis). Alternatively a low amount can mean an amountthat is less than 50%, such as less than 20%, less than 10%, less than5%, or less than 1% of the typical amount of the element/composition incorresponding compositions, methods, etc.

In aspects, one or more compounds of a composition providing a DOSpreservative effect can also provide one or more additional DOS effects,such as chelation effect, buffering effect, penetration enhancementeffect, etc.

In aspects, a “preservative” is a compound which detectably orsignificantly enhance stability of the composition(s), such as thestability of the one or more quinolone antibiotic componentconstituents, one or more anti-inflammatory compound constituents, orboth, reduces the number(s)/amount(s) of detectable/significantimpurities over the course of a storage under room temperature oraccelerated storage conditions, detectably or significantly reduceantimicrobial activity (e.g., within the composition), or anycombination of any or all thereof. In aspects, one or morepreservative(s) are present in composition(s) of the invention whichdetectably or significantly enhance stability of the composition(s),such as the stability of the one or more antimicrobial compounds, one ormore anti-inflammatory compounds, reduces the amount of impurities, orany combination of any or all thereof, such as providing for acomposition which is stable under room temperature storage conditions,e.g., providing for compositions which retain at least 90% of the one ormore quinolone antibiotic component constituents and at least 90% of theone or more anti-inflammatory steroid component constituents when storedat about 25° C.+/−2° C. and about 40% relative humidity, at about 40° C.and not more than 25% relative humidity, or both (ophthalmic product),or, e.g., 25° C. and 60% relative humidity or at 40° C. and 75% relativehumidity for 3 months (injectable product), for at least about one monthsuch as ≥˜2 months or such as ≥˜3 months or more. In aspects,compositions provided by the invention comprises one or morepreservatives in anti-microbially effective amount(s) which candetectably or significantly inhibit microbial growth.

In aspects, an “antimicrobial effective amount” of a preservative isdetermined by performing preservative efficacy tests or antimicrobialeffectiveness tests known in the art. In aspects, such tests aredescribed in, e.g., chapter 51 of the United States Pharmacopoeia29-National Formulary 24 (USP 29-NF 24). In aspects, composition(s)provided by the invention comprise one or more preservatives in anamount within the concentration ranges described in one or more standardreference books such as the most recent edition of Remington'sPharmaceutical Sciences, Handbook of Pharmaceutical Excipients 5^(th)ed. or 6^(th) ed., or Handbook of Pharmaceutical Excipients (9^(th)ed.), Sheskey et al. (ISBN 9780 85711 375 7) (2020).

For example, composition(s) provided by the invention comprise one ormore preservatives which detectably or significantly improve thestability of the one or more quinolone antibiotic component constituentsor one or more anti-inflammatory compound constituents, enhancesquinolone antibiotic component or anti-inflammatory effectiveness,prevent detectable or significant anti-microbial growth within thecomposition(s), or any or all thereof, at a period of at least 2 weekspost manufacturing, such as at a period ≥˜3 weeks, ≥˜1 month, ≥˜6 weeks,≥˜2 months, ≥˜10 weeks, ≥˜3 months, ≥˜14 weeks, ≥˜4 months, ≥˜18 weeks,≥˜5 months, ≥˜22 weeks, ≥˜6 months, or more (e.g., about 3-36 months,about 6-36 months, about 4-36 months, about 18-36 months, about 12-24months, about 6-24 months, or about 12-36 months).

In aspects, the invention provides composition(s) comprisingophthalmologically suitable preservative(s) effective (e.g., agentscapable of demonstrating one or more of the characteristics of apreservative described above in the context of a composition of theinvention) at pH range of between, e.g., ˜5.5-˜9.5, such as between˜6.0-˜9.0, e.g., or, e.g., ˜6.5-˜8.5. In aspects, a preservative of thecomposition(s) herein does not detectably or significantly negativelyimpact any other component of the formulation, such as, e.g., they donot detectably or significantly reduce the efficacy or functionality ofany one or more quinolone antibiotic component constituents,anti-inflammatory compound constituents (e.g., reduceinfection-reducing/treating effect or reduce anti-inflammatory effect),or any other API or excipient present or which may be present in thecomposition.

In aspects any ophthalmologically suitable and pharmaceuticallyacceptable preservative is used. In aspects, exemplary preservative(s)present in a composition described herein comprise effective amount(s)of, e.g., benzoic acid; hydrogen peroxide; sorbic acid; biguanides;quaternary ammonium salts such as benzalkonium chloride and benzethoniumchloride; cationic compounds such as chlorhexidine gluconate;p-hydroxybenzoates such as methyl p-hydroxybenzoate, ethylp-hydroxybenzoate, propyl p-hydroxybenzoate and butyl p-hydroxybenzoate;alcohol compounds such as chlorobutanol and benzyl alcohol; sodiumdehydroacetate; thiomersal (e.g., stabilized thimerosal, and other suchas, e.g., benzoic acid, benzyl alcohol, benzyl paraben, bronopol, butylparaben, cetrimide, cetylpryidinium chloride, chlorohexidine,chlorocresol, chloroxylenol, cresol, ethyl alcohol, ethyl paraben,ethylparaben, glycerin, hexetidine, imidurea, isobutyl paraben,meta-cresol, phenol, phenoxyethanol, phenylethyl alcohol, phenylmucuricnitrate, p-hydroxybenzoic acid esters, polyhexamethylene biguanide,potassium sorbate, propyl paraben, propylene glycol, sodium benzoate,sodium perborate, sodium propionate, sorbic acid, sodium citrate,benzalkonium chloride, benzethonium chloride, benzoic acid, benzylalcohol, benzyl paraben, bronopol, butyl paraben, cetrimide,cetylpyridinium chloride, chlorobutanol, chlorhexidine, chlorocresol,chloroxylenol, cresol, ethyl alcohol, ethyl paraben, ethylparaben,glycerin, hexetidine, imidurea, isobutyl paraben, meta-cresol, methylparaben, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol,phenylmercuric nitrate, p-hydroxybenzoic acid esters, polyhexamethylenebiguanide, potassium sorbate, propyl paraben, propylene glycol, sodiumbenzoate, sodium perborate, sodium propionate, sorbic acid, stabilizedthimerosal, and/or thimerosal etc., or any ophthalmologically acceptablesalts thereof, or combinations of any ≥2 of such compounds, orequivalents thereof.

In aspects, compositions comprise sodium citrate. In aspects, sodiumcitrate can provide one or more activities in addition to acting as apreservative, such as, e.g., providing buffering activity,emulsification activity, sequestration activity, or any combinationthereof.

In aspects, composition(s) provided by the invention comprise one ormore quaternary ammonium compounds, such as, e.g., benzalkoniumchlorides (abbreviated herein as BKC, and which is often abbreviated inthe art as BAC, BAK, or BZK). Benzalkonium chlorides may also bereferred to as alkyl dimethyl benzyl ammonium chlorides (ADBAC), alkyldimethyl (phenylmethyl) chlorides, or ammonium alkyl dimethyl benzylchlorides. In aspects, BKC can serve as a penetration enhancer,preservative, solubilizer, or any combination thereof. That is, inaspects, BKC can provide a detectable or significant increase in thepenetration, e.g., the bioavailability, of one or more ingredients ofthe composition(s) or both, can provide preservation qualities such asthose described in this section or in the art, or, e.g., can detectablyor significantly improve upon the solubilization of any one or moreAPIs, such as any one or more quinolone antibiotic componentconstituents, one or more anti-inflammatory steroid componentconstituents, or a combination thereof.

In this and any other excipient aspect of the invention, the inventionalso can be characterized as comprising a “means” for preservingcomposition(s) of the invention. In such a respect, any knownequivalents of such named agents can also be, e.g., are, incorporatedinto compositions or methods of the invention. As with other sectionssimilar described herein any of the components of the invention can be,where suitable, described as means (e.g., the above-described suspensionagents/components can be described as API suspension means or means forsuspending the active pharmaceutical ingredient(s) of the composition.

In aspects, compositions comprise between about 0.1-15 mg/mL of apreservative, such as, e.g., sodium citrate, such as e.g., between˜0.1-14.5 mg/mL, ˜0.1-14 mg/mL, ˜0.1-˜13.5 mg/mL, ˜0.1-˜13 mg/mL,˜0.1-˜12.5 mg/mL, ˜0.1-˜12 mg/mL, ˜0.1-˜11.5 mg/mL, ˜0.1-˜11 mg/mL,˜0.1-˜10.5 mg/mL, or, e.g., ˜0.1-˜10 mg/mL, such as, e.g., ˜0.2-˜15mg/mL, ˜0.3-˜15 mg/mL, ˜0.4-˜15 mg/mL, ˜0.5-˜15 mg/mL, ˜0.6-˜15 mg/mL,˜0.7-15 mg/mL, ˜0.8-15 mg/mL, ˜0.9-15 mg/mL, ˜1-15 mg/mL, such as, e.g.,between ˜0.2-14 mg/mL, ˜0.4-13 mg/mL, ˜0.6-12 mg/mL, ˜0.8-˜11 mg/mL, or,e.g., between about 1-about 10 mg/mL of a preservative, such as, e.g.,sodium citrate.

In aspects, one or more preservatives, such as, e.g., benzalkoniumchloride, are present in compositions in an amount of between about0.01-0.1 mg/mL, such as, e.g., between ˜0.02-˜0.1 mg/mL, ˜0.03-˜0.1mg/mL, ˜0.04-˜0.1 mg/mL, or, e.g., ˜0.05-˜0.1 mg/mL, such as, e.g.,between ˜0.01-˜0.09 mg/mL, ˜0.01-˜0.08 mg/mL, ˜0.01-˜0.07 mg/mL,˜0.01-˜0.06 mg/mL, or, e.g., ˜0.01-˜0.05 mg/mL, as in between about˜0.02-˜0.09 mg/mL, ˜0.03-˜0.08 mg/mL, ˜0.04-˜0.07 mg/mL, ˜0.04-˜0.06mg/mL, or, e.g., about 0.05 mg/mL benzalkonium chloride.

In aspects, the total amount of preservative in the compositions isbetween about 0.1-about 15 mg/mL, such as, e.g. between ˜0.1-14.5 mg/mL,˜0.1-14 mg/mL, ˜0.1-˜13.5 mg/mL, ˜0.1-˜13 mg/mL, ˜0.1-˜12.5 mg/mL,˜0.1-˜12 mg/mL, ˜0.1-˜11.5 mg/mL, ˜0.1-˜11 mg/mL, ˜0.1-˜10.5 mg/mL, or,e.g., ˜0.1-˜10 mg/mL, such as, e.g., ˜0.2-˜15 mg/mL, ˜0.3-15 mg/mL,˜0.4-15 mg/mL, ˜0.5-15 mg/mL, ˜0.6-15 mg/mL, ˜0.7-15 mg/mL, ˜0.8-15mg/mL, ˜0.9-15 mg/mL, ˜1-˜15 mg/mL, such as, e.g., between ˜0.2-14mg/mL, ˜0.4-13 mg/mL, ˜0.6-12 mg/mL, ˜0.8-11 mg/mL, or, e.g., betweenabout 1-about 10 mg/mL of preservative(s).

Tonicity Agent(s)

In aspects, compositions comprise one or more ophthalmologicallysuitable tonicity agents. In alternative aspects, compositions providedby the invention do not comprise any component characterizable as atonicity agent. Herein, “tonicity agent” refers to a substance used inthe ophthalmic compositions to effectively adjust the composition of theformulation to be within a desired isotonic range, e.g., becharacterizable as being having an osmolality within a defined range,e.g., a range as provided below.

According to aspects, one or more tonicity agents are present incomposition(s) of the invention which detectably or significantly reduceirritability or increase tolerability of the ophthalmic composition(s)over the same composition lacking such a tonicity agent or having asignificantly different osmolality. In aspects, inclusion of a tonicityagent can provide a tonicity of the composition rendering a compositiontolerable (e.g., lacking clinically significant irritation or damage) bya recipient/recipient eye.

In aspects, tonicity agent(s) of the composition(s) herein do notdetectably or significantly negatively impact any other component of theformulation, such as, e.g., they do not detectably or significantlyreduce the efficacy of any one or more quinolone antibiotic components,any one or more anti-inflammatory steroid components, or any other APIor excipient present or which may be present in the composition.

In facets, any ophthalmologically suitable and pharmaceuticallyacceptable tonicity agent(s) is used in compositions. Examples thereofinclude ionic isotonic agents, non-ionic isotonic agents, and the like.Examples of the ionic isotonic agents include inorganic salts, organicsalts, electrolytes, etc. Examples of the inorganic salts include sodiumchloride, disodium phosphate, sodium dihydrogen phosphate, potassiumdihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, sodiumthiosulfate, magnesium sulfate, potassium chloride, calcium chloride,magnesium chloride, boric acid, borax, and the like. Examples of theorganic salts include potassium acetate, sodium acetate, sodium hydrogencarbonate, sodium carbonate, and the like. Examples of the non-ionicisotonic agents include polyhydric alcohols having two or more alcoholichydroxy groups in single molecules, and the like. Specific examples ofthe polyhydric alcohols include, for example, glycerol, propyleneglycol, polyethylene glycol, glucose, trehalose, mannitol, dextrose,sucrose, xylitol, sorbitol, etc., or combinations of any two or more ofsuch compounds.

In this and any other excipient aspect of the invention, the inventionalso can be characterized as comprising a “means” for performing thefunction(s) associated with a type of excipient (e.g., such agents canbe classified as “means for controlling tonicity” or “means forproviding tonicity” and the like). In such a respect, any knownequivalents of such named agents can also be incorporated intocompositions or methods of the invention. This principle appliesgenerally to any excipients and other components of compositions andsteps of methods described herein.

In aspects, one or more tonicity agent(s) can be present in thecompositions provided by the invention in an amount representing betweenabout 0.001 w/v. %-about 1.4 w/v. % of the composition, such as, e.g.,˜0.08 w/v. %-˜1.2 w/v. %, ˜0.06 w/v. %-˜1 w/v. %, ˜0.04 w/v. %-˜0.9 w/v.%, or, e.g., between ˜0.01 w/v. %-˜0.8 w/v. % of the composition.

Buffer(s)/Buffering Agent(s)

In aspects, compositions provided by the invention comprise one or morebuffering agents. In aspects, buffering agents are used to adjust the pHof a composition to a desirable range, such as, e.g., to a pH of betweenabout 5.5-about 9.5, such as between ˜6.0-˜9.0, e.g., or, e.g.,˜6.5-˜8.5.

In aspects, a buffering agent is any ophthalmologically suitablebuffering agent including, e.g., acetate, borate, carbonate, citrate,tris, succinate, maleate, histidine, and phosphate buffering agents, orany ophthalmologically suitable derivatives, e.g., salts thereof, orcombinations of any two or more such compounds, or equivalents thereof.In aspects, a buffering agent is sodium citrate.

In certain aspects, compositions comprise sodium citrate. In aspects,sodium citrate can provide one or more activities in addition to actingas a buffering agent, such as, e.g., providing preservative activity,emulsification activity, sequestration activity, or any combinationthereof.

In this and any other excipient aspect of the invention, the inventionalso can be characterized as comprising a “means” for bufferingcomposition(s). In such a respect, any known equivalents of such namedagents can also be, e.g., are, incorporated into compositions or methodsof the invention.

In aspects, one or more buffering agents, such as, e.g., sodium citrate,is present in compositions in an amount of between about 0.5-20 mg/mL,such as, e.g., between ˜0.6-˜20 mg/mL, ˜0.7-˜20 mg/mL, ˜0.8-˜20 mg/mL,˜0.9-˜20 mg/mL, or, e.g., ˜1-˜20 mg/mL, such as, e.g., ˜0.5-˜19 mg/mL,˜0.5-˜18 mg/mL, ˜0.5-˜17 mg/mL, ˜0.5-˜16 mg/mL, ˜0.5-˜15 mg/mL, ˜0.5-˜14mg/mL, ˜0.5-˜13 mg/mL, ˜0.5-˜12 mg/mL, ˜0.5-˜11 mg/mL, or ˜0.5-˜10mg/mL, such as, e.g., between ˜0.6-˜18 mg/mL, ˜0.7-˜16 mg/mL, ˜0.8-˜14mg/mL, ˜0.9-˜12 mg/mL, or, e.g., between about 1-about 10 mg/mL.

pH Adjusting Agent(s)

In aspects, the pH of the composition(s) provided by the invention isadjusted using one or more ophthalmologically suitable pH adjustingagent(s). In aspects, the composition(s) provided by the inventioncomprise such one or more pH adjusting agent(s). In alternative aspects,compositions provided by the invention do not comprise any componentthat is a pH adjusting agent.

Herein, a “pH adjusting agent” is an acidifying or alkalizing agent usedto significantly lower or raise the pH (potential hydrogen) of thecomposition to a target value. In aspects, a pH adjusting agent is anagent which, alone, is incapable of providing a buffering capacity ofthe composition. In aspects, a pH adjusting agent is not accompanied bya corresponding acid or base to provide a buffering capacity to thecomposition. In aspects, an acidifying pH adjusting agent is present tolower the pH, while an alkalizing agent is present to raise the pH to atarget level. In aspects, an acidifying agent is characterizable as astrong acid. In aspects, an alkalizing agent is characterizable as astrong base. In aspects, a pH adjusting agent is added during themanufacturing process of the composition(s) to adjust the pH of thecomposition prior to final packaging.

According to aspects, one or more pH adjusting agents are present incomposition(s) of the invention in an amount and of a nature of whichprovide the resulting composition with a pH of between about 5.5-9.5,such as, e.g., between ˜5-˜9.4, ˜5-˜9.3, ˜5-˜9.2, ˜5-˜9.1, ˜5-˜9,˜5-˜8.9, ˜5-˜8.8, ˜5-˜8.7, ˜5-˜8.6, or, e.g., ˜5-˜8.5, or, e.g.,˜5.1-˜9.5, or ˜5.2-˜9.5, ˜5.4-˜9.5, ˜5.5-˜9.5, ˜5.6-˜9.5, ˜5.7-˜9.5,˜5.8-˜9.5, ˜5.9-˜9.5, ˜6-˜9.5, ˜6.1-˜9.5, ˜6.2-˜9.5, ˜6.3-˜9.5,˜6.4-˜9.5, or, e.g., ˜6.5-˜9.5, such as, e.g., ˜5.7-˜9.2, ˜6-˜8.9,˜6.1-˜8.8, ˜6.2-˜8.7, ˜6.3-˜8.6, ˜6.4-˜8.6, or, e.g., ˜6.5-˜8.5.

In aspects, pH adjusting agent(s) of the composition(s) herein do notdetectably or significantly negatively impact any other component of theformulation, such as, e.g., they do not detectably or significantlyreduce the efficacy of any one or more quinolone antibiotic components,anti-inflammatory steroid components (e.g., reduce microbial inhibitioneffect or reduce anti-inflammatory effect), or any other API orexcipient present in a composition.

In aspects any ophthalmologically suitable and pharmaceuticallyacceptable pH adjusting agent is used. In aspects, exemplary pHadjusting agent(s) in a composition comprise any suitable pH adjustingagents commonly used and known in the art, such as, e.g., an acid suchas a strong acid or, e.g., a base such as a strong base. In aspects, apH adjusting agent is, e.g., a mineral acid such as sodium hydroxidehydrochloric acid (HCl) or sodium hydroxide (NaOH), such as, forexample, ˜1N HCl or ˜1N NaOH (1N being the concentration of the agentadded to the composition(s) to adjust the pH of the composition(s)).

In this and any other excipient aspect of the invention, the inventionalso can be characterized as comprising a “means” for adjusting pH ofcomposition(s) of the invention. In such a respect, any knownequivalents of such named agents can also be, e.g., are, incorporatedinto compositions or methods of the invention.

In aspects, one or more pH adjusting agent(s) can be present in thecompositions provided by the invention in an amount effective inproviding the target pH. In aspects, such an amount can be considered a“trace amount,” e.g., less than ˜0.005 w/v. %, <0.004 w/v. %, <˜0.003w/v. %, <0.002 w/v. %, e.g., <˜0.001 w/v. %. In aspects, such an amountcan be an amount representing between about 0-about 0.01 w/v. %. Inaspects, one or more pH adjusting agent(s) can be present in thecompositions provided by the invent ion in an amount effective inproviding the target pH, such amounts representing between about 0-about0.1%, such as, e.g., about 0.01%, ˜0.02%, ˜0.03%, ˜0.04%, ˜0.05%,˜0.06%, ˜0.07%, ˜0.08%, or, e.g., ˜0.09%.

Surfactant(s)

In aspects, compositions comprise one or more ophthalmologicallysuitable surfactants. Such aspects also are somewhat described above inconnection with surfactants that also can be characterized as suspensionagents (e.g., polysorbate 80). In alternative aspects, compositionsprovided by the invention do not comprise any component characterizableas a surfactant.

The term “surfactant” typically refers to a substance used in theophthalmic compositions to DOS reduce surface tension of thecomposition(s), DOS increase surface spreading (e.g., wetting) or both.In aspects, a surfactant DOS improves dispersion of suspended particleswithin compositions herein over the dispersion of suspended particles incompositions lacking a surfactant. As noted, such agents are oftencharacterized as or are closely related to agents described assolubilizers, dispersing agents, or both. Any agent exhibiting one ormore of such characteristics can be present where desired/suitable.

According to aspects, one or more surfactants are present incomposition(s) of the invention which detectably or significantlyincrease the spreading/wetting of the ophthalmic composition(s) over thesame composition lacking such a surfactant or having a significantlydifferent surface tension-related property.

In aspects, surfactant(s) of the composition(s) herein do not DOSnegatively impact any other component of the formulation, such as, e.g.,they do not DOS reduce the efficacy of any one or more quinoloneantibiotic components, any one or more anti-inflammatory steroidcomponents, or any other API or excipient present or which may bepresent in the composition.

In facets, any ophthalmologically suitable and pharmaceuticallyacceptable surfactant(s) are used in compositions. Exemplarysurfactants(s) include, e.g., lecithin and lecithin derivativesincluding pure phospholipids such as, e.g., soya phosphatidyl choline)and mixed phospholipids, sodium cholate, and hydroxylatedphospholipids/hydroxylated lecithin; glycerol fatty acid estersincluding polyglycerol fatty acid esters, polyglycerol polyricinoleate,hydrogenated castor oils and propylene glycol fatty acid esters (suchas, e.g., polyoxyethyleneglycerol triricinoleate, Cremophor® EL(macrogol-1500-glyceroltriricinoleate), Cremophor® RH-40, and monobutylglycerol); polysorbates such as polysorbate-80; sorbitan fatty acidesters including sorbitan monolaurate and sorbitan monoleate;polyoxyethylene sorbitan fatty acid esters including polyethylene glycolsorbitan monolaurate and polyethylene glycol sorbitan monooleate; etc.,including propylene glycol, PEGs (e.g., PEG 200, PEG 400, PEG 3350,etc.), and cosurfactants such as alkanols (e.g., ethanol, propanol,butanol, etc.), alkane-diols (e.g., 1,2-propane diol, 1,2-butane diol,etc.), and alkane-polyols (glycerol, glucitol, polyethylene glycol,etc.), or derivatives thereof or combinations of any two or more of suchcompounds.

In aspects, compositions comprise one or more non-ionic surfactants. Inaspects, a non-ionic surfactant can be, e.g., any ophthalmologicallysuitable non-ionic surfactant. In aspects, the non-ionic surfactant is,e.g., a polysorbate, a polyoxyl-ethylated castor oil (such as, e.g.,Cremophor® EL, or e.g., Cremophor® RH-40), or, e.g., is a componentcomprising a combination thereof.

In aspects, compositions comprise one or more ionic surfactants. Inaspects, compositions comprise one or more non-ionic surfactants and oneor more ionic surfactants. In aspects, a non-ionic surfactant canprovide one or more other DOS functions. In aspects, a non-ionicsurfactant can exhibit, suspension-related properties. In aspects, anon-ionic surfactant is also a non-ionic suspension agent. In aspects,the non-ionic surfactant, non-ionic suspension agent is a polysorbatecompound. In aspects, the polysorbate compound is polysorbate-80. Inaspects, a non-ionic surfactant, non-ionic suspension agent is apolyoxyl-ethylated castor oil. In aspects, a polyoxyl-ethylated castoroil is a Cremophor® EL or Cremophor® RH-40.

In aspects, compositions comprise 2 or more surfactants, such as, e.g.,2 or more ionic surfactants, 2 or more non-ionic surfactants, or, e.g.,at least one ionic surfactant and at least one non-ionic surfactant. Inaspects, compositions can comprise ˜2, ˜3, or ˜4 or more ionicsurfactants. In aspects, compositions can comprise ˜2, ˜3, or ˜4 or moreionic surfactants. In aspects, compositions can comprise a single ionicsurfactant in addition to 2 or more non-ionic surfactants. In aspects,compositions can comprise a single non-ionic surfactant in addition to 2or more ionic surfactants. For example, in aspects compositions comprisea polysorbate compound (such as, e.g., polysorbate-80), apolyoxyl-ethylated castor oil (such as, e.g., a Cremophor® such asCremophor® EL or Cremophor® RH-40 or their equivalents), or both apolysorbate and a polyoxyl-ethylated castor oil.

In aspects, one or more surfactant(s), which as stated, in aspects canalso provide DOS suspension properties, e.g., polysorbate-80, is presentin the compositions provided by the invention in an amount representingbetween about 1-20 mg/mL, such as between ˜2-˜20 mg/mL, ˜2-˜18 mg/mL,˜2-˜16 mg/mL, ˜2-˜14 mg/mL, ˜2-˜12 mg/mL, or, e.g., ˜2-˜10 mg/mL, suchas, e.g., between ˜4-˜20 mg/mL, ˜6-˜20 mg/mL, ˜8-˜20 mg/mL, ˜10-˜20mg/mL, as in, e.g., between ˜2-˜18 mg/mL, ˜4-˜16 mg/mL, ˜6-˜14 mg/mL,˜8-˜12 mg/mL, ˜9-˜11 mg/mL, or, e.g., about 10 mg/mL. In aspects, thesurfactant is polysorbate-80.

In aspects, one or more non-ionic surfactant(s), which, as stated, inaspects can also provide DOS suspension properties, is an effectiveamount of polyoxyl-ethylated castor oil, wherein the polyoxyl-ethylatedcastor oil is present in an amount of between about 0.05-about 1.5 wt.%, such as, e.g., between ˜0.05-˜1.4 wt. %, ˜0.05-˜1.5 wt. %, ˜0.05-˜1.3wt. % ˜0.05-˜1.2 wt. % ˜0.05-˜1.1 wt. %, or ˜0.05-˜1 wt. %, such as,e.g., between about ˜0.06-˜1.5 wt. %, ˜0.07-˜1.5 wt. %, ˜0.08-˜1.5 wt.%, ˜0.09-˜1.5 wt. %, ˜0.1-˜1.5 wt. %, such as, e.g., between about˜0.02-˜1.4 wt. %, ˜0.04-˜1.3 wt. %, ˜0.06-˜1.2 wt. %, or, e.g.,˜0.08-˜1.1 wt. %, such as, e.g., ˜0.1-˜1 wt. %.

In this and any other excipient aspect of the invention, the inventionalso can be characterized as comprising a “means” for performing thefunction(s) associated with a type of excipient (e.g., such agents canbe classified as “means for controlling surface tension”, “means forimproving spreadability”, “means for increasing wettability”, or“surfactant means” and the like). In such a respect, any knownequivalents of such named agents can also be, e.g., are, incorporatedinto compositions or methods of the invention.

In aspects, one or more surfactants, such as, e.g., sodium citrate, ispresent in compositions in an amount of between about 0.5-20 mg/mL, suchas, e.g., between ˜0.6-˜20 mg/mL, ˜0.7-˜20 mg/mL, ˜0.8-˜20 mg/mL,˜0.9-˜20 mg/mL, or, e.g., ˜1-˜20 mg/mL, such as, e.g., ˜0.5-˜19 mg/mL,˜0.5-˜18 mg/mL, ˜0.5-˜17 mg/mL, ˜0.5-˜16 mg/mL, ˜0.5-˜15 mg/mL, ˜0.5-˜14mg/mL, ˜0.5-13 mg/mL, ˜0.5-˜12 mg/mL, ˜0.5-˜11 mg/mL, or ˜0.5-˜10 mg/mL,such as, e.g., between ˜0.6-18 mg/mL, ˜0.7-˜16 mg/mL, ˜0.8-˜14 mg/mL,˜0.9-˜12 mg/mL, or, e.g., between about 1-about 10 mg/mL.

Viscoelasticity Agent(s)

In aspects, compositions comprise one or more compounds which exhibitDOS viscoelastic behavior or impart DOS viscoelastic characteristics toa composition in which they are present. Viscoelastic behavior is acombination of a compound providing elasticity behavior, e.g., returningto an original shape, size, or both after having been altered due toexposure to a sufficient force (e.g., a polymer returning to an originalshape, size, or both after having been stretched), and viscous behavior,e.g., providing a DOS resistance to flow or motion. In aspects, aviscoelasticity agent can be any pharmaceutically acceptable orophthalmologically suitable viscoelasticity agent, such as, e.g.,chondroitin sulfate, hyaluronic acid, derivatives of cellulose includingmethylcellulose, polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone (PVP), carbomers (weakly crosslinked polyacrylic acids),collagen, and the like, or any ophthalmologically suitable derivatives,e.g., salts thereof (e.g., sodium hyaluronate), or combinations of anytwo or more such compounds, or equivalents thereof.

In aspects, a viscoelasticity agent demonstrates ≥1 additional DOSfunctions within a composition, such as, e.g., demonstrating DOSsuspension activity. For example, hyaluronic acid is characterizable asboth a viscoelasticity agent and a suspension agent.

In aspects, viscoelasticity agent(s) acts synergistically with one ormore other viscoelasticity agents. That is, for example, a viscosity ofthe composition can be established which is DOS, such as, e.g.,substantially, higher than would be expected mathematically when definedamounts of two or more viscoelasticity agents are provided. For example,in aspects, compositions comprise hyaluronic acid and chondroitinsulfate. In such aspects, compositions can be formulated such that theviscosity of the composition is measurably higher than would be expectedmathematically based on the individual quantities of each agent, suchas, e.g., as much as about 10, ˜11, ˜12, ˜13, ˜14, ˜15, ˜16, ˜17, ˜18,˜19, or ˜20× higher than what would be expected mathematically based onthe individual quantities of each agent.

In this and any other excipient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providingviscoelastic property(ies) of the invention. In such a respect, anyknown equivalents of such named agents can also be, e.g., are,incorporated into compositions or methods of the invention.

In aspects, one or more viscoelasticity agents, such as, e.g.,chondroitin sulfate is present in compositions in an amount representingbetween about 1-100 mg/mL, such as, e.g., between ˜1-˜90 mg/mL, ˜1-˜80mg/mL, ˜1-˜70 mg/mL, ˜1-˜60 mg/mL, or, e.g., ˜1-˜50 mg/mL, such as,e.g., between ˜2-˜100 mg/mL, ˜3-˜100 mg/mL, ˜4-˜100 mg/mL, ˜5-˜100mg/mL, as in, e.g., between ˜1.5-˜90 mg/mL, ˜2-˜80 mg/mL, ˜2.5-˜70mg/mL, ˜3-˜60 mg/mL, ˜3.5-˜50 mg/mL, ˜4-˜50 mg/mL, ˜4.5-˜50 mg/mL, or,e.g., between ˜5-˜50 mg/mL mg/mL of chondroitin sulfate.

In aspects, compositions comprise between about 1-40 mg/mL of aviscoelastic agent, such as, e.g., hyaluronic acid, such as, e.g.,comprising between about between ˜1-˜38 mg/mL, ˜1-˜36 mg/mL, ˜1-˜34mg/mL, ˜1-˜32 mg/mL, ˜1-˜30 mg/mL, ˜1-˜28 mg/mL, ˜1-˜26 mg/mL, ˜1-˜24mg/mL, ˜1-˜22 mg/mL, ˜1-˜24 mg/mL, ˜1-˜22 mg/mL, ˜1-˜20 mg/mL, as in,for example, ˜1.1 to ˜40 mg/mL, ˜1.2-˜40 mg/mL, ˜1.3-40 mg/mL, ˜1.4-40mg/mL, ˜1.5-˜40 mg/mL, ˜1.6-˜40 mg/mL, ˜1.7-˜40 mg/mL, ˜1.8-˜40 mg/mL,or, e.g., ˜1.9-˜40 mg/mL, as in, for example, between ˜1.1-˜38 mg/mL,˜1.2-˜36 mg/mL, ˜1.3-˜34 mg/mL, ˜1.4-˜32 mg/mL, ˜1.5-˜30 mg/mL, ˜1.6-˜28mg/mL, ˜1.7-˜26 mg/mL, ˜1.8-˜24 mg/mL, ˜1.9-˜22 mg/mL, or, e.g., ˜2.0-20mg/mL of hyaluronic acid.

In aspects, compositions comprise between about 2-about 150 mg/mL of oneor more viscoelasticity agents, such as, e.g., chondroitin sulfate andhyaluronic acid, such as, e.g., between ˜2-˜150 mg/mL, ˜3-˜150 mg/mL,˜4-˜150 mg/mL, ˜5-˜150 mg/mL, ˜6-˜150 mg/mL, or, e.g., ˜7-˜150 mg/mL,such as, e.g., between ˜2-˜140 mg/mL, ˜2-˜130 mg/mL, ˜2-˜120 mg/mL,˜2-˜100 mg/mL, ˜2-˜100 mg/mL, ˜2-˜90 mg/mL, ˜2-˜80 mg/mL, or, e.g.,˜2-˜70 mg/mL, such as, e.g., ˜3-˜130 mg/mL, ˜4-˜110 mg/mL, ˜5-˜100mg/mL, ˜6-˜80 mg/mL, or, e.g., between ˜7-˜70 mg/mL of one or moreviscoelasticity agents.

Sequestering Agent(s)

In aspects, compositions provided by the invention comprise one or moreophthalmologically suitable sequestration agents (e.g., sequesteringcompounds). In alternative aspects, compositions provided by theinvention do not comprise any component characterizable as asequestering compound. Terms such as “sequestration agent” or“sequestering compound” generally refer to a substance used in theophthalmic compositions to link metal ions or molecules together to formchelates (however, such different terminology can be used to describecompounds differing from chelating compounds in their ability to bindtogether two or more metal ions).

In aspects, a sequestration agent can be any ophthalmologically suitablesequestration agent, such as, e.g., aminocarboxylic acid-based products,phosphates and phosphonates, hydroxy carboxylates, polyacrylates, sugaracrylates, acetic acid, oxalic acid, gluconic acid, citric acid, sodiumcitrate, etc., or any ophthalmologically acceptable derivative, e.g.,salts thereof, or combinations of any two or more such compounds, orequivalents thereof.

In certain aspects, compositions comprise sodium citrate. In aspects,sodium citrate can provide one or more activities in addition to actingas a sequestration agent, such as, e.g., providing buffering activity,emulsification activity, preservative activity, or any combinationthereof.

In this and any other excipient aspect of the invention, the inventionalso can be characterized as comprising a “means” for sequestration ofingredients of composition(s) of the invention. In such a respect, anyknown equivalents of such named agents can also be, e.g., are,incorporated into compositions or methods of the invention.

In aspects, one or more sequestration agents, such as, e.g., sodiumcitrate, is present in compositions in an amount of between about 0.5-20mg/mL, such as, e.g., between ˜0.6-˜20 mg/mL, ˜0.7-˜20 mg/mL, ˜0.8-˜20mg/mL, ˜0.9-˜20 mg/mL, or, e.g., ˜1-˜20 mg/mL, such as, e.g., ˜0.5-˜19mg/mL, ˜0.5-˜18 mg/mL, ˜0.5-˜17 mg/mL, ˜0.5-˜16 mg/mL, ˜0.5-˜15 mg/mL,˜0.5-˜14 mg/mL, ˜0.5-˜13 mg/mL, ˜0.5-˜12 mg/mL, ˜0.5-˜11 mg/mL, or˜0.5-˜10 mg/mL, such as, e.g., between ˜0.6-˜18 mg/mL, ˜0.7-˜16 mg/mL,˜0.8-˜14 mg/mL, ˜0.9-˜12 mg/mL, or, e.g., between about 1-about 10mg/mL.

Vehicle Component(s)

In aspects, compositions provided by the invention comprise anophthalmologically suitable vehicle/carrier component, the vehiclecomponent, in aspects, comprising one or more ophthalmologicallysuitable vehicle constituents/agents.

In certain aspects, a composition comprising a vehicle can beadministered directly to the eye, as, in aspects, a vehicle provides theingredients in a form and at a concentration wherein their applicationto the eye is safe and suitable for suitable for ocular administration.In aspects, composition(s) provided by the invention are typicallyprovided with a vehicle component.

According to aspects, one or more vehicle constituents are present in avehicle component of a composition in a sufficient amount to deliver theeffective amounts of API(s) and, if present, one or more excipients.

In aspects, the invention provides for a vehicle component wherein thevehicle does not detectably or significantly adversely affect thestability of the composition, efficacy of the composition, orcompatibility of ingredients of the composition, etc., at a period of atleast about 2 weeks, e.g., at a period of ˜1 month, ≥˜6 weeks, ≥˜2months, ≥˜10 weeks, ≥˜3 months, ≥˜14 weeks, ≥˜4 months, ≥˜18 weeks, ≥˜5months, ≥˜22 months, ≥˜6 months, or even longer (e.g., 2-36 months, 6-36months, 12-24 months, or similar ranges provided with respect to otheringredients/compositions described herein, etc.).

In aspects, a vehicle component in a composition provided by theinvention is an ophthalmologically suitable vehicle capable of servingas a vehicle of a composition having a pH of, e.g., between about˜5.0-˜9.0, such as between ˜5.5-˜8.8, e.g., ˜6-8.6, or, e.g., betweenabout ˜5.5-˜8.5. In aspects, the vehicle, does not have a pH lower thanabout 5.0. In aspects, a vehicle of the composition(s) herein does notdetectably or significantly negatively impact any other component of theformulation, such as, e.g., a vehicle does not detectably orsignificantly reduce the efficacy of any one or more quinoloneantibiotic components, any one or more anti-inflammatory steroidcomponents, or both (e.g., reduce microbial inhibitory effect or reduceanti-inflammatory effect), or any other API or excipient present in thecomposition.

In aspects any ophthalmologically suitable and pharmaceuticallyacceptable vehicle is used in a composition provided by the invention.In aspects, exemplary vehicles used in a composition described hereincomprise, e.g., a lipid vehicle, a gel vehicle, an oil-based vehicle, anemulsion vehicle, an emulsifier-containing vehicle that forms anemulsion when mixed with other components, or, a solution vehicle, e.g.,an aqueous solution vehicle. In aspects, the carrier is an aqueouscarrier. In aspects, the carrier is mostly, generally only, essentiallyonly, substantially only, or only composed of water, e.g., water forinjection (WFI) (a sterile, solute-free preparation of distilled water).In alternative aspects, other ophthalmologically suitable aqueouscarriers which do not adversely affect the stability of thecomposition(s) may be used, such as, e.g., deionized water.

In aspects, a vehicle is an aqueous or a non-aqueous vehicle; inaspects, the vehicle is a combination vehicle, comprised of acombination two or more vehicles described above, such as a combinationof an aqueous and a non-aqueous vehicle.

In aspects, a composition can be characterized as comprising “vehiclemeans” comprising such types of vehicles or known equivalents thereof,or combinations of any thereof.

According to aspects, the vehicle does not comprise any detectable,significant, or intentionally added amount of any deuterated vehicle or,in aspects, any deuteration, e.g., the vehicle can mostly, generally, oronly comprise non-deuterated water or otherwise lack any deuteratedvehicles, other excipients, or components in general. In alternativeaspects, a composition comprises one or more components/ingredients,such as, e.g., a vehicle ingredient, which comprises deuteration (e.g.,comprises the intentional replacement of one or more hydrogen atoms on avehicle compound with one or more deuterium atoms), such as, e.g.,deuterated water.

In this and any other excipient aspect of the invention, the inventionalso can be characterized as comprising a vehicle “means” of theinvention (e.g., means of carrying and delivering ingredients of thecomposition(s). In such a respect, any known equivalents of such namedagents can also be, e.g., are, incorporated into compositions or methodsof the invention.

In aspects, a vehicle can be present in the compositions provided by theinvention in an amount representing at least about 50 w/v %, ≥˜55 w/v %,≥˜60 w/v %, ≥˜65 w/v %, ≥˜70 w/v %, 275 w/v %, ≥˜80 w/v %, ≥˜85 w/v %,≥˜90 w/v %, ≥˜95 w/v %, ≥˜97 w/v %, ≥˜98 w/v %, ≥˜99 w/v % of thecomposition. In aspects, the vehicle is mostly, is generally, isessentially, or is entirely composed of water.

Penetration Enhancer(s)

In aspects, compositions provided by the invention compriseophthalmologically suitable penetration enhancer(s). In alternativeaspects, compositions provided by the invention do not comprise anycomponent characterizable as a penetration enhancer. In general, a“penetration enhancer” refers to a substance used in the ophthalmiccompositions to penetration of one or more compounds of thecompositions, e.g., increasing the access of one or more compounds ofthe composition to deeper layers or regions of ocular tissue in anamount more than, or at a rate faster than, the compound would otherwisebe able to penetrate ocular tissue.

In aspects, a penetration enhancer can be any ophthalmologicallysuitable penetration enhancer, such as, e.g., quaternary ammoniumcompounds polyoxyethylene sorbitan fatty acid esters, tocopherolpolyethylene glycol succinate (TPGS), poly-arginine, polyserine,tromethamine (tris), sesame seed oil or oils having similar compositionsand functional characteristics suitable for ophthalmic use, or anyophthalmologically suitable derivatives, e.g., salts thereof, orcombinations of any two or more such compounds, or equivalents thereof.Polyoxyethylene sorbitan fatty acid esters can include but may not belimited to polyoxyethylene sorbitan laurate (polysorbate 20),polyoxyethylene sorbitan palmitate (polysorbate 40), a polyoxyethylenesorbitan stearate (polysorbate 60), a polyoxyethylene sorbitan tristearate (polysorbate 65). In respects, polyoxyethylene sorbitan fattyacid ester ingredients can be a polyoxyethylene sorbitanoleate/polyoxyethylene sorbitan mono-oleate ester (e.g., polysorbate80). This exemplifies how certain ingredients can perform >2 or evenmore than >3 functions or fulfill >2 or >3 categories of agents in acomposition (e.g., polysorbate 80 can be characterized as a surfactant,a suspension agent, and a penetration enhancer).

In aspects, composition(s) provided by the invention comprise one ormore quaternary ammonium compounds, such as, e.g., benzalkoniumchlorides (abbreviated herein as BKC, and which is often abbreviated inthe art as BAC, BAK, or BZK). Benzalkonium chlorides may also bereferred to as alkyl dimethyl benzyl ammonium chlorides (ADBAC), alkyldimethyl (phenylmethyl) chlorides, or ammonium alkyl dimethyl benzylchlorides. In aspects, BKC can serve as a penetration enhancer,preservative, solubilizer, or any combination thereof. That is, inaspects, BKC can provide a detectable or significant increase in thepenetration, e.g., the bioavailability, of one or more ingredients ofthe composition(s) or both, can provide preservation qualities such asthose described in this section or in the art, or, e.g., can detectablyor significantly improve upon the solubilization of any one or moreAPIs, such as any one or more quinolone antibiotic componentconstituents, one or more anti-inflammatory steroid componentconstituents, or a combination thereof.

In this and any other excipient aspect of the invention, the inventionalso can be characterized as comprising a “means” for increasing one ormore constituents of the composition(s) of the invention. In such arespect, any known equivalents of such named agents can also be, e.g.,are, incorporated into compositions or methods of the invention.

In aspects, one or more penetration enhancers, such as, e.g.,benzalkonium chloride, are present in compositions in an amount ofbetween about 0.01-0.1 mg/mL, such as, e.g., between ˜0.02-˜0.1 mg/mL,˜0.03-˜0.1 mg/mL, ˜0.04-˜0.1 mg/mL, or, e.g., ˜0.05-˜0.1 mg/mL, such as,e.g., between ˜0.01-˜0.09 mg/mL, ˜0.01-˜0.08 mg/mL, ˜0.01-˜0.07 mg/mL,˜0.01-˜0.06 mg/mL, or, e.g., ˜0.01-˜0.05 mg/mL, as in between about˜0.02-˜0.09 mg/mL, ˜0.03-˜0.08 mg/mL, ˜0.04-˜0.07 mg/mL, ˜0.04-˜0.06mg/mL, or, e.g., about 0.05 mg/mL benzalkonium chloride.

In aspects, one or more penetration enhancers, such as, e.g.,polysorbate-80 or a polyoxy-ethylated castor oil, is present in thecompositions provided by the invention in an amount representing betweenabout 1-20 mg/mL, such as between ˜2-˜20 mg/mL, ˜2-˜18 mg/mL, ˜2-˜16mg/mL, ˜2-˜14 mg/mL, ˜2-˜12 mg/mL, or, e.g., ˜2-˜10 mg/mL, such as,e.g., between ˜4-˜20 mg/mL, ˜6-˜20 mg/mL, ˜8-˜20 mg/mL, ˜10-˜20 mg/mL,as in, e.g., between ˜2-˜18 mg/mL, ˜4-˜16 mg/mL, ˜6-˜14 mg/mL, ˜8-˜12mg/mL, ˜9-˜11 mg/mL, or, e.g., about 10 mg/mL. In aspects, thepenetration enhancer is polysorbate-80.

In aspects, the total concentration of penetration enhancer(s) incompositions provided by the invention is between about 1-20 mg/mL, suchas between ˜2-˜20 mg/mL, ˜2-˜18 mg/mL, ˜2-˜16 mg/mL, ˜2-14 mg/mL, ˜2-˜12mg/mL, or, e.g., ˜2-˜10 mg/mL, such as, e.g., between ˜4-˜20 mg/mL,˜6-˜20 mg/mL, ˜8-˜20 mg/mL, ˜10-˜20 mg/mL, as in, e.g., between ˜2-˜18mg/mL, ˜4-˜16 mg/mL, ˜6-˜14 mg/mL, ˜8-˜12 mg/mL, ˜9-˜11 mg/mL, or, e.g.,about 10-about 11 mg/mL.

Antioxidant(s)

In aspects, compositions provided by the invention comprise one or moreophthalmologically suitable antioxidants. In alternative aspects,compositions provided by the invention do not comprise any componentcharacterizable as an antioxidant.

An “antioxidant” is typically understood as referring to a substancethat preferentially reacts with oxygen, thereby detectably orsignificantly protecting other components of a composition to which itis added from premature degradation due to oxidation (e.g., protectingAPIs that is known to be detectably/significantly susceptible tooxidation).

According to aspects, one or more antioxidant compounds are present incomposition(s) of the invention which detectably or significantlyimprove API stability or reduce the amount of impurities, such as, e.g.,providing for a composition which is stable under room temperaturestorage conditions, e.g., retains ≥90% of the one or more quinoloneantibiotic component constituents and ≥90% of the one or moreanti-inflammatory compounds when stored at about 25° C.+/−2° C. andabout 40% relative humidity, at about 40° C. and not more than 25%relative humidity, or both, (ophthalmic product), or, e.g., 25° C. and60% relative humidity or at 40° C. and 75% relative humidity for 3months (injectable product), for at least about one month such as ≥˜2months or such as ≥˜3 months, ≥˜4 months, ≥˜5 months, or, e.g., ≥˜6months.

For example, composition(s) provided by the invention can comprise oneor more antioxidant agents which detectably improve the stability of theone or more quinolone antibiotic component constituents, one or moreanti-inflammatory steroid component constituents, reduces the amount ofimpurities, enhances preservative effectiveness, or any or all thereof,at a period of at least 2 weeks post manufacturing, such as at a period≥˜3 weeks, ≥˜1 month, ≥˜6 weeks, ≥˜22 months, ≥˜10 weeks, ≥˜3 months,≥˜14 weeks, ≥˜4 months, ≥˜18 weeks, ≥˜5 months, ≥˜22 weeks, ≥˜6 months,or for even longer periods (e.g., 3-24, 3-18, 3-12, 3-36, 4-12, 4-24,4-36, 6-12, 6-18, 6-24, or 6-36 months).

In aspects, the invention provides composition(s) comprising one or moreophthalmologically suitable antioxidant agents effective at pH range ofbetween ˜5.5-˜9.5, such as between ˜6.0-˜9.0, e.g., or, e.g., ˜6.5-˜8.5.In aspects, antioxidant compound(s) of the composition(s) herein do notdetectably or significantly negatively impact any other component of theformulation, such as, e.g., they do not detectably or significantlyreduce the efficacy of any one or more antimicrobial compoundconstituents, anti-inflammatory steroid component constituents (e.g.,reduce microbial inhibitory effect or anti-inflammatory effect), or anyother API or excipient present or which may be present in thecomposition.

In aspects any ophthalmologically suitable and pharmaceuticallyacceptable antioxidant is used in methods of the invention/incorporatedin compositions of the invention, in any suitably effective amount(s).In aspects, exemplary antioxidant(s) in a composition described hereincomprise, e.g., sodium ascorbate, ascorbic acid, thiamine, pyridoxine,histidine, cysteine, glutathione, sodium bisulphite, sodium sulphite,sodium metabisulphite, sodium thiosulphite, sodium formaldehydesulphoxylate, acetylcysteine, cysteine, thioglycerol, thioglycollicacid, thiolactic acid, thieurea, dihithreitol, propyl gallate, butylatedhydroxyanisole, butylated hydroxytoluene, tertiary butyl hydroquinone,ascorbyl palmitate, nordihydroguaiaretic acid and alpha-tocopherol, anyophthalmologically acceptable derivative, e.g., salts thereof, orcombinations of any two or more such compounds.

In this and any other excipient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providingantioxidant activity to composition(s) of the invention. In such arespect, any known equivalents of such named agents can also be, e.g.,are, incorporated into compositions or methods of the invention.

In aspects, one or more antioxidant compound(s)/agent(s) can be presentin the compositions provided by the invention in an amount representingbetween about 0.001 w/v. %-about 2 w/v. % of the composition, such as,e.g., ˜0.001 w/v. %-˜1.8 w/v. %, ˜0.001 w/v. %-˜1.6 w/v. %, ˜0.001 w/v.%-˜1.4 w/v. %, ˜0.001 w/v. %-1.2 w/v. %, ˜0.08 w/v. %-˜1 w/v. %, or.e.g., ˜0.05-˜1 w/v. % of the composition.

Additional APIs (or Lack Thereof)

As noted above, in aspects, compositions provided by the inventioncomprise quinolone antibiotic component(s), anti-inflammatory steroidcomponent(s), suspension component(s), and no detectable or significantamounts of any additional active pharmaceutical ingredients.

In certain aspects, compositions provided by the invention comprisequinolone antibiotic component(s), anti-inflammatory steroidcomponent(s), suspension component(s), and an effective and suitableamount of at least one additional API.

According to aspects, compositions of the invention can comprise one ormore additional ophthalmologically suitable APIs in addition to thequinolone antibiotic component(s), anti-inflammatory steroidcomponent(s), and suspension component(s) in any effective amount whichprovides for the API to affect the desired effect. In aspects, anadditional API can be present in an amount effective in detectably orsignificantly increasing the efficacy of the quinolone antibioticcomponent, detectably or significantly increasing the efficacy of theanti-inflammatory steroid component, or detectably or significantlyincreasing the therapeutic usefulness or clinical efficacy of thecomposition, e.g., demonstrating a detectable or significant beneficialeffect in the recipient of the composition. In aspects, the one or moreadditional active pharmaceutical ingredients can provide a detectable orsignificant increase in anti-inflammatory strength or activity of thecomposition. In aspects, the one or more additional APIs can provide adetectable or significant increase in the microbial inhibition orkilling strength or activity of the composition. In aspects, the one ormore additional APIs can provide a detectable or significant, e.g.,clinically significant effect, different from antimicrobial oranti-inflammatory activity.

In aspects, composition(s) provided by the invention can comprise one ormore additional APIs in addition to quinolone antibiotic component(s),anti-inflammatory steroid component(s), and suspension component(s),wherein the one or more additional APIs are stable within thecomposition(s) at a pH of between, e.g., ˜5.0-˜9.0, such as between˜6.0-˜9.0, e.g., ˜6.5-˜8.5, for a period of at least 2 weeks postmanufacturing, such as at a period ≥˜3 weeks, ≥˜1 month, ≥˜6 weeks, ≥˜2months, ≥˜10 weeks, ≥˜3 months, ≥˜14 weeks, ≥˜4 months, ≥˜18 weeks, ≥˜5months, ≥˜22 weeks, ≥˜6 months, or more.

In aspects, any one or more additional APIs of the composition(s)provided by the invention do not detectably or significantly negativelyimpact any other component of the formulation, such as, e.g., they donot detectably or significantly reduce the efficacy of any one or morequinolone antibiotic component constituent(s), anti-inflammatoryconstituent(s), (e.g., reduce microbial inhibition or killing effect, orreduce anti-inflammatory effect) or any other API or excipient presentin the composition.

In aspects any ophthalmologically suitable and pharmaceuticallyacceptable API can be used. In aspects, APIs present in a compositionprovided by the invention in addition to one constituents of thequinolone antibiotic component, or anti-inflammatory steroid component,can be any one or more of, e.g., antineoplastic agent, anti-allergicagent, glaucoma-treating agent, intraocular pressure reducing agent,etc., such as any ophthalmologically suitable compound which imparts abenefit to the eye of the recipient other than anti-microbial oranti-inflammatory effect. In aspects, compositions provided by theinvention can comprise one or more pharmaceutically acceptable andophthalmological anti-microbial agents, e.g., an antibacterial, asynthetic antibacterial, an antifungal, a synthetic antifungal, whereinthe anti-microbial agent is present in an amount effective in detectablyor significantly treating, preventing, or inhibiting development of orprogression of a microbial growth, e.g., a bacterial growth or a fungalgrowth.

In one aspect, the invention provides compositions comprising one ormore antimicrobials, e.g., one or more antibiotics, other than theabove-described quinolone antibiotic API(s). In certain aspects,suitable antibacterial/antibiotics can be any ophthalmologicallysuitable antibacterial/antibiotic. In aspects, suitableantibacterial/antibiotics for combination therapy are, for example,aminoglycosides for example amikacin, apramycin, arbekacin,bambermycins, butirosin, dibekacin, dihydrostreptomycin, fortimicin(s),gentamicin, tobramycin, isepamicin, kanamycin, micronomicin, neomycin,neomycin undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin,spectinomycin, streptomycin, trospectomycin; amphenicois for exampleazidamfenicol, chloramphenicol, florfenicol, thiamphenicol), ansamycins(e.g., rifamide, rifampin, rifamycin sv, rifapentine, rifaximin;beta-lactams for example carbacephems include loracarbef; carbapenemsfor example biapenem, imipenem, meropenem, panipenem; cephalosporins forexample cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone,cefazolin, cefcapene pivoxil, cefclidin, cefdinir, cefditoren, cefepime,cefetamet, cefixime, cefmenoxime, cefodizime, cefonicid, cefoperazone,ceforanide, cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide,cefpirome, cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin,ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone,cefuroxime, ceifuzonam, cephacetrile sodium, cephalexin, cephaloglycin,cephaloridine, cephalosporin, cephalothin, cephapirin sodium,cephradine, pivcefalexin; cephamycins for example cefbuperazone,cefmetazole, cefininox, cefotetan, cefoxitin; monobactams for exampleaztreonam, carumonam, tigemonam), oxacephems, flomoxef, moxalactam;penicillins for example amdinocillin, amdinocillin pivoxil, amoxicillin,ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin,bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium,carbenicillin, carindacillin, clometocillin, cloxacillin, cyclacillin,dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin,lenampicillin, metampicillin, methicillin sodium, mezlocillin, nafcillinsodium, oxacillin, penamecillin, penethamate hydriodide, penicillin gbenethamine, penicillin g benzathine, penicillin g benzhydrylamine,penicillin g calcium, penicillin g hydrabamine, penicillin g potassium,penicillin g procaine, penicillin n, penicillin o, penicillin v,penicillin v benzathine, penicillin v hydrabamine, penimepicycline,phenethicillin potassium, piperacillin, pivampicillin, propicillin,quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin,ticarcillin and other like ritipenem; lincosamides for exampleclindamycin and lincomycin; macrolides for example azithromycin,carbomycin, clarithromycin, dirithromycin, erythromycin, erythromycinacistrate, erythromycin estolate, erythromycin glucoheptonate,erythromycin lactobionate, erythromycin propionate, erythromycinstearate, josamycin, leucomycins, midecamycins, miokamycin,oleandomycin, primycin, rokitamycin, rosaramicin, roxithromycin,spiramycin, troleandomycin; polypeptides for example amphomycin,bacitracin, capreomycin, colistin, enduracidin, enviomycin, fusafungine,gramicidin s, gramicidin(s), mikamycin, polymyxin, pristinamycin,ristocetin, teicoplanin, thiostrepton, tuberactinomycin, tyrocidine,tyrothricin, vancomycin, viomycin, virginiamycin and zinc bacitracin;tetracyclines for example apicycline, chlortetracycline, clomocycline,demeclocycline, doxycycline, guamecycline, lymecycline, meclocycline,methacycline, minocycline, oxytetracycline, penimepicycline,pipacycline, rolitetracycline, sancycline and, e.g., tetracycline, andpharmaceutically acceptable salts thereof, and mixtures thereof. Inaspects, suitable synthetic antibacterials suitable for combinationtherapy are, for example, 2,4-diaminopyrimidines for examplebrodimoprim, tetroxoprim, trimethoprim; nitrofurans for examplefuraltadone, furazolium chloride, nifuradene, nifuratel, nifurfoline,nifurpirinol, nifurprazine, nifurtoinol, nitrofurantoin; quinolones andanalogs for example cinoxacin, ciprofloxacin, clinafloxacin, difloxacin,enoxacin, fleroxacin, flumequine, grepafloxacin, lomefloxacin,miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxacin,oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid,rosoxacin, rufloxacin, sparfloxacin, temafloxacin, tosufloxacin,trovafloxacin; sulfonamides for example acetyl sulfamethoxypyrazine,benzylsulfamide, chloramine-b, chloramine-t, dichloramine-t,N2-Formylsulfisomidine, N4-β-d-Glucosylsulfanilamide, mafenide,4′-(methylsulfamoyl)sulfanilanilide, noprylsulfamide,phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine,succinylsulfathiazole, sulfabenzamide, sulfacetamide,sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine,sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole,sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfarnerazine,sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine,sulfamethoxazole, sulfamethoxypyridazine, sulfametrole,sulfamidocchrysoidine, sulfamoxole, sulfanilamide,4-sulfanilamidosalicylic acid, N4-sulfanilylsulfanilamide,sulfanilylurea, N-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine,sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine,sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea,sulfatolamide, sulfisomidine, sulfisoxazole; sulfones for exampleacedapsone, acediasulfone, acetosulfone sodium, dapsone,diathymosulfone, glucosulfone sodium, solasulfone, succisulfone,sulfanilic acid, p-sulfanilylbenzylamine, sulfoxone sodium,thiazolsulfone; and others like clofoctol, hexedine, methenamine,methenamine anhydromethylene-citrate, methenamine hippurate, methenaminemandelate, methenamine sulfosalicylate, nitroxoline, taurolidine, and,e.g., xibornol, and pharmaceutically acceptable salts thereof, andmixtures thereof. In general, any description of an additional APIherein with respect to compositions implicitly provides support for theuse of such additional API(s) in combination therapy methods, whereinsuch agents are administered/delivered separately to a subject, such asa patient, in combination with composition(s) of the invention (and viceversa). In aspects, antifungal agents suitable for combinationcompositions or combination therapy with compositions of the inventionare, for example, polyenes e.g., amphotericin b, candicidin,dennostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin,mepartricin, natamycin, nystatin, pecilocin, perimycin, azaserine,griseofulvin, oligomycins, neomycin undecylenate, pyrrolnitrin,siccanin, tubercidin, and, e.g., viridin, and pharmaceuticallyacceptable salts thereof, and mixtures thereof. Examples of suitablesynthetic antifungals include, e.g., allylamines for example butenafine,naftifine, terbinafine, imidazoles for example bifonazole, butoconazole,chlordantoin, chlormiidazole, clotrimazole, econazole, enilconazole,fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole,miconazole, omoconazole, oxiconazole nitrate, sertaconazole,sulconazole, tioconazole; thiocarbamates for example tolciclate,tolindate, tolnaftate; triazoles for example fluconazole, itraconazole,saperconazole, terconazole and others like acrisorcin, amorolfine,biphenamine, bromosalicylchloranilide, buclosamide, calcium propionate,chlorphenesin, ciclopirox, cloxyquin, coparaffinate, diamthazoledihydrochloride, exalamide, flucytosine, halethazole, hexetidine,loflucarban, nifuratel, potassium iodide, propionic acid, pyrithione,salicylanilide, sodium propionate, sulbentine, tenonitrozole, triacetin,ujothion, undecylenic acid, and, e.g., zinc propionate, andpharmaceutically acceptable salts thereof, and mixtures thereof. Inaspects, antineoplastic agents suitable for combination therapy are, forexample, ophthalmologically suitable forms of mitomycin C orfluorouracil (5FU), or Intron A, or ophthalmologically suitable forms ofmethotrexate, cytarabine (Ara-C), thiotepa, chlorambucil, dacarbazine,or temozolamide, etc. In aspects, anti-allergic agents suitable forcombination therapy or combination compositions are, for example,ophthalmologically suitable antihistamines (e.g., levocabastine,emedastine, bilastine, cetirizine, etc.), ophthalmologically suitablemast-cell stabilizers (e.g., cromolyn, nedocromil, etc.),ophthalmologically suitable dual-activity agents (providing bothantihistamine and mast-cell inhibition activity, such as, e.g.,olopatadine, bepotastine, alcaftadine, etc.), ophthalmologicallysuitable corticosteroids (e.g., loteprednol etabonate, loteprednol,mapracorat, prednisolone acetate, prednisolone phosphate, dexamethasone,etc.), ophthalmologically suitable non-steroidal anti-inflammatory drugs(such as, e.g., those disclosed above, or, e.g., specifically be, e.g.,diclofenac sodium, nepafenac, etc.), ophthalmologically suitabledecongestants (e.g., brimonidine, etc.), ophthalmologically suitableimmunomodulators (e.g., cyclosporine A, tacrolimus, etc.) and otherssuch as ophthalmologically suitable cannabis preparations,immunobiologicals, etc. In certain aspects, intraocularpressure-treating agents or glaucoma-treating agents suitable forcombination therapy are, for example, beta blockers (e.g., nonselectivebeta blockers such as, e.g., timolol maleate, levobunolol, carteolol,metipranolol, etc. or, e.g., selective beta blockers such as, e.g.,betaxolol, etc.), mimotics (e.g., pilocarpine, etc.), carbonic anhydraseinhibitors (e.g., dorzolamide, brinzolamide, etc.), sympathomimetics(e.g., epinephrine-like sympathomimetics such as, e.g., dipivefrin, etc.or, e.g., clonidine-like sympathomimetics such as, e.g., brimonidine,apraclonidine, etc.), prostaglandin analogs (e.g., latanoprost,travoprost, tafluprost, bimatoprost, latanoprosten bunod, etc.), etc. Incertain aspects, antiviral agents suitable for combination therapy are,for example, idoxuridine (IDU), iododesoxycytidine (IDC), vidarabine(Ara-A), trifluridine (ITT), aciclovir, ganciclovir, trifluridine,idoxuridine, ophthalmologically suitable formulations of valganciclovir,foscarnet, etc. In aspects, anti-mycotic agents suitable for combinationtherapy are, for example, ophthalmologically suitable polyenes (e.g.,amphotericin B (AMB), nystatin, nytamycin (NTM), etc.),ophthalmologically suitable azoles (e.g., imidazoles or triazoles,including, e.g., miconazole (MCZ), econazole (ECZ), ketoconazole (KCZ),itraconazole (ICZ), fluconazole), voriconazole, posaconazole (PCZ),etc.), ophthalmologically suitable pyrimidines (e.g., 5-fluorocystine(5-FC), flucytosine, etc.), ophthalmologically suitable echinocandins(e.g., caspofungin (CFG), micafungin (MFG), etc.), etc.

Optionally Excluded Ingredients

In aspects, compositions provided by the invention can be described byingredients which are not present. In aspects, compositions herein donot comprise any one or more of a co-polymer. In aspects, compositionsherein do not comprise any one or more of a block copolymer. In aspects,compositions exclude block copolymers of poly(ethylene oxide) andpoly(propylene oxide). In aspects, compositions herein do not compriseany one or more of specific block copolymers. In aspects, compositionsherein do not comprise non-ionic block copolymers. In aspects,compositions herein do not comprise a non-ionicpolyoxyethylene-polyoxypropylene block copolymer having the chemicalstructure:HO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H,wherein x is an integer having the value of at least 8 (such as, e.g.,≥8, ≥9, ≥10, ≥11, ≥12 or more) and y is an integer having the value ofat least 38 (such as, e.g., ≥38, ≥39, ≥40, ≥41, ≥42, ≥43, ≥44, ≥45 ormore). In specific aspects, compositions exclude Poloxamer-407 (BASF),the difunctional block copolymer terminating in primary hydroxy groupsmarketed as Pluronic® F-127 (BASF Corporation), and the non-ionicdi-hydroxyfunctional block copolymer (poly alkylene oxide blockcopolymer) marketed as Synperonic™ PE/F 127 (Croda Healthcare).

In aspects, compositions herein do no comprise xanthan gum. In aspects,compositions do not comprise hydroxypropyl methyl cellulose.

Means/Steps for Performing Functions

In aspects, compositions provided by the invention comprise one or moremeans for performing one or more specific functions and methods of theinvention include steps for performing functions. In general, anyelement described herein as a “means” for performing a function canalso, wherever suitable, serve as a “step for” performing a function inthe context of methods of the invention, and vice versa. E.g., acomponent described herein as a means for preserving a composition alsosimultaneously and implicitly supports a method of making such acomposition comprising a step of preserving a composition and a kitcomprising a means for delivering a composition implicitly andsimultaneously provides a step for delivering the composition comprisingthe use of such delivery means.

In one aspect, compositions provided by the invention comprise means forchelation, such means for chelation detectably or significantlyimproving the stability of the one or more quinolone antibioticcomponent constituents, detectably or significantly improving thestability of one or more anti-inflammatory steroid componentconstituents, detectably enhancing the effectiveness of one or morepreservatives, or any combination thereof (“chelation means”). Supportfor chelation means can be found in, e.g., the section entitled,“Chelating Agent(s).”

In one aspect, compositions comprise means for preserving thecomposition(s), e.g., detectably or significantly inhibit microbialgrowth, detectably or significantly reducing the number of impurities ordetectably or significantly improving the stability of the compositionssuch that compositions remain safe and suitable for administration afterstorage of at least about 1 month, e.g., ˜2 months, or e.g., ˜3 monthsor more after manufacturing at room temperature (25° C. and about 40%relative humidity, about 40° C. and no more than 25% relative humidity,or both (ophthalmic product), or, e.g., 25° C. and 60% relative humidityor at 40° C. and 75% relative humidity for 3 months (injectableproduct)) (“preservation means”). Support for preservation means can befound in, e.g., the section entitled, “Preservative(s).”

In one aspect, compositions provided by the invention comprise means forproviding a suitable tonicity of the composition(s), providing asuitable osmolality of the composition(s), e.g., means for providingcomposition(s) which do not cause detectable or significant ocularirritation due to tonicity when provided according to instructions(“tonicity means”). Support for tonicity means can be found in, e.g.,the section entitled, “Tonicity Agent(s).”

In aspects, compositions provided by the invention comprise means forbuffering the addition of, or buffering the presence of (if/when suchcompositions are placed into an environment having or compositionsdevelop or are exposed to), elements or compositions of a different pHor which are capable of otherwise detectably or significantly modifyingthe pH of the compositions (“buffering means”). Exemplary bufferingmeans are described in, e.g., the section entitled, “Buffer(s)/BufferingAgent(s).”

In one aspect, compositions provided by the invention comprise means foradjusting the pH of the composition(s), providing a suitable or targetpH of the composition(s) of between about, e.g., ˜6-9, such as, e.g.,˜6.2-˜8.8, or, e.g., between about 6.5-about 8.5, such as, between about6.8-about 7.2 (e.g., 7.0±0.2) (“pH adjusting means”). Support for pHadjusting means can be found in, e.g., the section entitled, “pHAdjusting Agent(s).”

In one aspect, compositions provided by the invention comprise means formodifying the surface tension of the compositions which in aspectsprovides means for increasing the spreading, e.g., the wetting, of theophthalmic compositions (“surfactant means”). Support for surfactantmeans can be found in, e.g., the section entitled, “Surfactant(s).”

In one aspect, compositions provided by the invention comprise means formodifying the viscoelasticity of the composition(s), providingviscoelastic protection of the eye or ocular features (“viscoelasticitymeans”). Support for viscoelasticity means can be found in, e.g., thesection entitled, “Viscoelasticity Agent(s).”

In one aspect, compositions provided by the invention comprise means forlinking metal ions or molecules together to form chelates (complexring-like structures which tend to be stable and resist decomposition),doing so by binding to multiple metal ions at a time, limiting theirability to react with other compounds (“sequestration means”).“Sequestration means” are distinct from “chelation means” in that“sequestration means” bind multiple metal ions at once while “chelationmeans” bind a single metal ion at a time. Support for “sequestrationmeans” can be found in, e.g., the section entitled, “SequesteringAgent(s).”

In one aspect, compositions provided by the invention comprise means forproviding compositions of the invention, e.g., delivering APIs and otheringredients of the composition, as, e.g., liquid compositions; e.g.,providing a carrier or vehicle for the API's and any one or more otherexcipients of the composition(s) (“vehicle means”). Support for vehiclemeans can be found in, e.g., the section entitled, “VehicleComponent(s).”

In one aspect, compositions provided by the invention comprise means forincreasing the penetration of one or more compounds of the compositions,e.g., increasing the access of one or more compounds of the compositionto deeper layers or regions of ocular tissue (“penetration means”).Support for penetration means can be found in, e.g., the sectionentitled, “Penetration Enhancer(s).”

In one aspect, compositions provided by the invention comprise means forprotecting APIs from oxidation, e.g., means for providing antioxidantprotection of API(s), such means for antioxidant protection of API(s)detectably or significantly improving the stability of the one or morequinolone antibiotic component constituents, detectably or significantlyimproving the stability of one or more anti-inflammatory steroidcomponent constituents, detectably or significantly reducing impuritiesdetected at time points 2 weeks, 1 months, 2 months, or 3 months or moreafter manufacturing, or any combination thereof (“antioxidant means”).Support for antioxidant means can be found in, e.g., the sectionentitled, “Antioxidant(s).”

In one aspect, compositions provided by the invention comprise means forproviding compositions of the invention with detectable or significantincreases in clinically relevant anti-inflammatory effect over thatprovided by the quinolone antibiotic component alone (“anti-inflammatorymeans”). Support for anti-inflammatory means can be found in, e.g., thesection entitled, “Anti-inflammatory Component.”

In one aspect, compositions provided by the invention comprise means fordetectably or significantly treating, preventing, or inhibitingdevelopment of, or progression of, microbial growth, e.g., bacterialgrowth, such as that present in an ocular infection (“antimicrobialmeans”). In aspects, such antimicrobial means for inhibiting microbialgrowth can be present in the composition in addition to (e.g.,separately from) any one or more other preservation means (e.g., meansfor detectably or significantly reducing impurities or detectably orsignificantly extending stability over a storage period) which may bepresent in the composition. Support for antimicrobial means can be foundin, e.g., the section entitled, “Quinolone antibiotic component.”

General Characteristics of Compositions Suspension

In aspects, compositions provided by the invention are characterizableas suspensions. In general, a “suspension” is intended to take on itsstandard meaning in the art, that is a heterogeneous mixture of a fluidcomprising solid particles which are not dissolved but are rathermaintained dispersed throughout the fluid. Particles of suspensions aregenerally capable of settling out of the fluid given enough time or whenplaced under certain conditions. In aspects, compositions hereincomprise a suspension component which aids in extending the length oftime particles of the composition remain in suspension without DOSsettling or flocculating. Suspension components andcompounds/agents/constituents thereof are discussed in detail elsewhereherein.

In aspects, compositions provided by the invention are capable ofmaintaining particles therein, e.g., particles of one or more steroidalanti-inflammatory compound(s), for a period of at least about 5 minutes,e.g., ≥˜10 minutes, ≥˜20 minutes, ≥˜30 minutes, ≥˜45 minutes, ≥˜1 hour,≥˜3 hours, ≥˜6 hours, ≥˜12 hours, ≥˜18 hours, ≥˜24 hours, ≥˜2 days, ≥˜3days, ≥˜4 days, ≥˜5 days, ≥˜6 days, ≥˜7 days, ≥˜2 weeks, ≥˜3 weeks, ≥˜4weeks, ≥˜2 months, ≥˜3 months, ≥˜4 months, ≥˜5 months, or, e.g., ≥˜6months or longer.

In aspects, compositions herein effectively maintain ≥1 non-dissolvedcompounds in suspension such that they are unable to negativelyinterfere with one or more other compounds of the composition, such thatthey are unable to DOS negatively impact the uniformity of thecomposition, e.g., they are unable to detectably or significantlyagglomerate/flocculate (here, the two terms are used synonymously), orboth. In aspects, an exemplary defining characteristic of the inventivecompositions herein is their ability to maintain both one or morefluoroquinolone compound(s) and one or more anti-inflammatorycompound(s) (e.g., steroidal, non-steroidal, or both steroidal andnon-steroidal anti-inflammatory compounds) effectively in suspensionsuch that the composition maintains sufficient deflocculation to makethe compositions suitable for intraocular use for a period of at leastabout 3 months when stored under standard storage conditions (e.g., atabout 25° C. and about 40% relative humidity, or, e.g., at about 40° C.and no more than 25% relative humidity, or both (ophthalmic product),or, e.g., 25° C. and 60% relative humidity or at 40° C. and 75% relativehumidity for 3 months (injectable product)).

In aspects, compositions are characterized as not exhibiting sustainedphysical stability, in terms of, for example, detectable or significantflocculation, coagulation, or clumping, which cannot be overcome throughmoderate agitation, such as manual agitation for times describedelsewhere herein. In other words, in aspects, compositions do notexhibit detectable or significant sustained coagulation, clumping, orflocculation.

Particle Size

In aspects, compositions provided by the invention comprise particles insuspension. In aspects, the particles in suspension have an averagediameter in any direction of less than 5 μm, such as, e.g., <˜4.5 μm,<˜4 μm, <˜3.5 μm, <˜3 μm, <˜2.5 μm, <˜2 μm, <˜1.5 μm, <1 μm, or evenless, such as <˜0.5 μm, e.g., between about 0.5 μm-about 3 μm, as inbetween ˜0.5-˜2.5 μm, ˜0.5-˜2 μm, ˜1.5-˜2.5 μm, or ˜0.5-˜1 μm, such as,e.g., ˜1-˜3 μm, ˜0.5-˜1.5 μm, or, e.g., ˜2-˜2.5 μm.

In aspects, compositions designed for delivery by injection, e.g., byintracameral injection, comprise a particle size of less than about 2μm, e.g., <˜1.75 μm, <˜1.5 μm, <˜1.25 μm, <1 μm, <˜0.75 μm, or, e.g.,<˜0.5 μm, as in between about 0.5-about 1.5 μm.

In aspects, compositions designed for delivery as drops (e.g., viastandard eye-drop administration methods known in the art) comprise aparticle size of less than about 5 μm, such as, e.g., <˜4.5 μm, <˜4 μm,<˜3.5 μm, <˜3 μm, <˜2.5 μm, or, e.g., <˜2 μm, such as between about2-about 3 μm.

In aspects, compositions comprising particles with an average size lessthan 5 μm, mostly comprising particles of less than 5 μm perform DOSbetter in terms of maintaining uniform size and/or shapecharacteristics, e.g., in the case of relatively uniform sized andsufficiently small particle compositions, over periods of time, such asthose described elsewhere (e.g., >1 month, >2 months, >3 months, >6months, >1 year, >18 months, or >2 years when maintained under typicalFDA stability testing conditions, as described elsewhere or known in theart). In aspects, particles can be defined by an absolute, typical, oraverage size or shape.

In one aspect, the particle size of particles in suspension incompositions herein cannot DOS block trabecular meshwork of the eye,e.g., cannot DOS restrict flow of aqueous humor out of the eye. That is,in aspects, particle size of particles, and particle size of any two ormore agglomerated particles, is sufficiently small so as to allow atleast about80%, >˜82%, >˜84%, >˜86%, >˜88%, >˜90%, >˜90%, >˜92%, >˜94%, >˜96%, >˜98%, >˜99%, >˜99.5%, >˜99.75%,or, e.g., ˜100% of unrestricted aqueous humor flow through thetrabecular meshwork of the eye.

In aspects, most, generally all, substantially all, or all agglomerationof particles, e.g., any flocculation of particles, is resolved byshaking the compositions for a minimum of about 10 seconds, such as,e.g., at least about ˜12 seconds, ˜14 seconds, ˜16 seconds, ˜18 seconds,˜20 seconds, ˜22 seconds, ˜24 seconds, ˜26 seconds, ˜28 seconds, ˜30seconds, such as, e.g., at least about ˜35 seconds, ˜40 seconds, ˜45seconds, ˜50 seconds, ˜55 seconds, or, e.g., ˜60 seconds. In aspects,most, generally all, substantially all, or all flocculation is resolvedby shaking for less than about 60 seconds, such as by shaking for <˜55seconds, <˜50 seconds, <˜45 seconds, <˜40 seconds, <˜35 seconds, <˜30seconds, <˜25 seconds, <˜20 seconds, <˜15 seconds, <˜10 seconds, or,e.g., by shaking for less than about 5 seconds. In aspects, shaking forsuch period(s) of time results in less than about 40%, <˜ 35%, <˜ 30%,<˜ 25%, <˜ 20%, <˜15%, <˜ 10%, or, e.g., <˜ 5% of the particles of thecomposition being flocculated, or, e.g., results in no DOS particleflocculation.

In one aspect, particles of composition(s) herein can be characterizedas being mostly, generally, or substantially uniform in size, shape, orboth, for example having mostly, generally, or substantially the samemaximum diameter in any single direction, or for example being mostly,generally, or substantially spherical or other shape.

Average Diameter or Maximum Dimension Size of Particles

One possible way to characterize compositions of the invention is theaverage maximum size of the particles in any one dimension or themaximum average diameter in the case of particles that are spheroid orspherical in shape. It is to be understood that these concepts can beinterchanged herein such that the description of any aspect with respectto a maximum average diameter, as applied to a spheroid particle forexample, is to be understood as providing corresponding support for anon-spheroid particle having an average maximum size in any onedimension of a corresponding size.

In one aspect, at least about 50%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 99%, orabout 100% of the particles in the composition have a maximum diameter(or average maximum dimension) of less than about 5 m, such as, e.g.,≤˜4.5 μm, ≤˜4 μm, ≤˜3.5 μm, ≤˜3 μm, ≤˜2.5 μm, ≤˜2 μm, ˜1.5 μm, ≤˜1 μm,or, e.g., even ≤˜0.5 μm. In one aspect, the size of at least about 75%,at least about 85%, at least about 92.5%, or at least about 97.5% of theparticles of the composition, or more, such as about 100% of theparticles of the composition, are between about 0.5-about 1.5 μm incompositions provided by injection and between about 2-about 3 μm incompositions provided by drops.

Size Distribution of Particles and Methods of Production

Compositions of the invention also can be characterized on the basis ofthe size distribution of particles in the composition. In this respectit is worth noting that many compositions of the invention will compriseparticles that vary in size due to differences that arise in themanufacturing process, handling, or for similar reasons. In aspects,compositions with relatively uniform sizes can offer advantageousproperties including in aiding in injectability of the composition,aiding in the suspension characteristics of the compositions, etc.

In aspects, particles of the compositions provided by the invention arerelatively uniform in size. The relative uniformity in particle size ofthe suspended particles of the compositions herein can be characterizedby describing the coefficient of variation in particle size in thecomposition. E.g., in aspects, the maximum particle diameter coefficientof variation (CV) of particles of the composition is less than about75%, <˜70%, <˜65%, <˜60%, <˜55%, <˜50%, <˜45%, <˜40%, <˜35%, <˜30%,<˜25%, <˜20%, <˜15%, <˜12.5%, <˜10%, or less than about 7.5%, e.g.,<˜7%, <˜6%, or <˜5%.

In aspects, particles of the compositions described herein can have asize distribution such that >20%, such as ≥˜22%, ≥˜24%, ≥˜26%, ≥˜28%,≥˜30%, ≥˜32%, ≥˜34%, ≥˜36%, ≥˜38%, ≥˜40%, ≥˜42%, ≥˜44%, ≥˜46% ≥˜48% or≥˜50%, such as ≥˜52%, ≥˜54%, ≥˜56%, ≥˜58%, ≥˜60%, ≥˜62%, ≥˜64%, ≥˜66%,≥˜68%, ≥˜70%, ≥˜72%, ≥˜74%, ≥≥˜76%, ≥≥˜78%, or ≥˜ 80% of the particlesof the composition have a maximum particle diameter that is within about75%, ˜70%, ˜65%, ˜60%, ˜65%, ˜50%, ˜48%, ˜46%, ˜44%, ˜42%, ˜40%, ˜38%,˜36%, ˜34%, ˜32%, ˜30%, ˜28%, ˜26%, ˜24%, ˜22%, ˜20%, ˜18%, ˜16%, ˜14%,˜12%, or, e.g., within ˜10% of the average particle diameter of theparticles in the composition. According to specific embodiments, atleast about 65% of the particles of the composition have a maximumparticle diameter that is within 35% of the average particle diameter ofthe particles in the composition. According to alternative specificembodiments, at least about 70% of the particles of the composition havea maximum particle diameter that is within about 33% of the averageparticle diameter of the particles in the composition. According to yetfurther embodiments, at least 33% of the particles have a maximumdiameter that is within about 15% of the average particle diameter ofparticles in the composition. In yet another embodiment, at least about40% of the particles have a maximum diameter that is within about 20% ofthe average particle diameter of the particles in the composition.

According to certain embodiments, less than about 50%, such as, <˜40%,<˜30%, <˜20%, <˜10%, or, e.g., <˜5% of the particles of compositionsherein have an average maximum dimension/diameter that is above 5 m.According to certain embodiments, less than about 50%, such as, <˜40%,<˜30%, <˜20%, <˜10%, or, e.g., <˜5% of the particles of compositionsherein have an average maximum dimension/diameter that is below 0.1 m.According to certain embodiments, compositions designed for injectioncomprise less than about 50%, such as, <˜40%, <˜30%, <˜20%, <˜10%, or,e.g., <˜5% of the particles having have an average maximumdimension/diameter that is above 2 μm or below 0.1 μm. According tocertain embodiments, compositions designed for administration by dropscomprise less than about 50%, such as, <˜40%, <˜30%, <˜20%, <˜10%, or,e.g., <˜5% of the particles having have an average maximumdimension/diameter that is above 4 μm or below 1 μm.

In some aspects, the particles of the inventive compositions canalternatively be described by their size relative to one another.According to certain embodiments, the particles in suspension withincompositions herein have an average maximum diameter which is less thanabout 5 μm and greater than about 0.1 μm, and at least about 85%, ≥90%,≥95%, or more (e.g., ≥97.5% or ≥˜99%) of the particles in suspensionhave an average maximum diameter that is within about 75%, ˜80%, ˜85%,˜90%, or within about ˜95% or more of the average maximum diameter of atleast about 75%, ˜80%, ˜85%, ˜90%, or ˜95% or more of the otherparticles in suspension.

In aspects, suspended particles of the compositions provided herein canalso or alternatively be characterizable based on the shape of some,most, largely all, substantially all, or all of the particles in thecomposition. In aspects, particles of the invention can have anysuitable shape. For example, the particles can have a “pollen” shape, asquircle shape, a disc shape, or other shape. In a typical aspect theparticles have a relatively spherical or spheroid shape. The uniformityof shape of particles can be determined by comparison of the dimensionsof the particles. In one aspect, the composition materially comprises,predominately comprises, largely consists of, substantially consists of,consists essentially of, or consists of particles having a relativelysimilar proportion in most dimensions, in at least 65% of dimensions, atleast 75% of dimensions, at least 90% of dimensions, or in alldimensions. Dimensions in this respect means dimensions in all planes ofthe particles' three-dimensional shapes. E.g., at least about 50%, atleast about 70%, at least about 85%, at least about 95%, or at leastabout 100% of the particles in aspects can be characterizable as havingthe same shape.

In aspects, particles will also have the same size, such that theproportions described above can be 1:1 or about 1:1. For example, wheremost, largely all, nearly all, or all of the particles in thecomposition are spherical/spheroid less than about 10% of particles cantypically have a maximum diameter that is more than 40% greater than theaverage diameter of particles in the composition or less than about 40%of the average diameter of particles in the composition. For example,<˜10%, <˜9%, <˜8%, <˜7%, <˜6%, <˜5%, <˜4%, <˜ 3%, <˜2%, or <˜1%, such as<˜0.9%, <˜0.8%, <˜0.7%, <˜0.6%, <˜0.5%, <˜0.4%, <˜0.3%, <˜0.2%, <˜0.1%,<˜0.05%, or less than about 0.01% of particles have a maximum diameterthat is more than about 40%, such as more about42%, >˜44%, >˜46%, >˜48%, >˜50%, >˜52%, >˜54%, >˜56%, >˜58%, or >˜60%,forexample >˜62%, >˜64%, >˜66%, >˜68%, >˜70%, >˜72%, >˜74%, >˜76%, >˜78%, >˜80%, >˜82%, >˜84%, >˜86%, >˜88%,or more than about 90%, for example >˜92%, >˜94%, >˜96%, >˜98%, or morethan approximately 99% larger or smaller than the average diameter ofparticles in the composition. According to one embodiment, less than 1%of particles have a maximum diameter that is more than 66% greater thanthe average diameter of particles in the composition or less than about66% of the average diameter of particles in the composition. Accordingto one embodiment, less than about 10% of the particles have a maximumdiameter more than 50% greater or less than about 50% less than theaverage diameter of particles in the composition.

In one exemplary aspect, the invention provides compositions in whichthe diameter of at least about 80% of the particles of the compositioncan vary by no more than about 5% in any direction. That is, forexample, >˜80%, for example >˜82%, >˜84%, >˜86%, >˜88%, or forexample >˜90%, >˜92%, >˜94%, >˜94%, >˜96%, >˜98%, >˜99% or at leastapproximately 99.5% of the particles of the present invention vary by nomore than about 15%, for example vary by <˜14%, <˜13%, <˜12%, <˜11%,<˜10%, <˜9%, <˜8%, <˜7%, <˜6%, <˜5%, <˜4%, or even less, for example<˜3%, <˜2% or vary by no more than 1% in any direction, conferring amostly spherical shape to the particles. According to specificembodiments, at least about 80% of the particles of the composition varyby no more than 15% in any direction. According to more specificembodiments, at least about 90% of the particles of the composition varyby no more than about 5% in any direction. According to one embodiment,at least about 80% of the particles of the composition vary by no morethan about 2% in any direction, and according to yet further specificembodiments, at least about 85% of the particles of the presentinvention vary by no more than about 1% in any direction.

In another aspect, the invention provides particles wherein the diameter(or average maximum dimension, average dimension, and/or average minimumdimension) of at least 80% of the particles of the composition (e.g., atleast about 90% of the particles or at least about 95% of the particles)varies by no more than 15% in any direction. In more particular aspectsat least about 85%, at least about 85%, or at least about 99% of theparticles have diameters that vary by 5% or less with respect to theaverage diameter of the particles in the composition. In still moreprecise aspects, at least about 50%, at least about 60%, at least about70%, at least about 85%, or at least about 95% of the particles can havediameters that are within about 2% of the average particle diameter oreven within ˜1% of the average particle diameter.

Corneal Contact Time

In aspects, compositions provided by the invention comprise one or moreingredients which DOS increase corneal contact time of the compositionover compositions lacking such a component. In aspects, such aningredient is characterizable as any one or more of a suspensioncomponent or constituent of a suspension component, a viscoelasticityagent, or, e.g., a surfactant. In aspects, such a component DOSdemonstrates two or more such functions, such as, e.g., a componentwhich DOS increases corneal contact time of the compositions ischaracterizable both as a suspension component or constituent of asuspension component, a surfactant, or both. For example, in aspects,compositions comprise a suspension component wherein the suspensioncomponent DOS increases corneal contact time over compositions lackingsuch a suspension component. In aspects, the suspension componentcomprises hyaluronic acid, methylcellulose, carboxymethylcellulose(CMC), hydroxyethylcellulose, hydroxypropyl methylcellulose, gelatin,acacia, povidone, polyvinylpyrrolidone, polysorbates (e.g.,polysorbate-80), polyoxyl-ethylated castor oil (e.g., Cremophor® EL orCremophor® RH-40), and polyethylene glycols (PEGs), such as, e.g., PEG400, PEG 3350, etc. or any ophthalmologically suitable derivative,prodrug, hydrate, salt, solvate, enantiomer, or polymorph thereof. Inaspects, such compounds increase corneal contact time.

In aspects, compositions comprise a surfactant, wherein the surfactantDOS increases corneal contact time over compositions lacking such asurfactant. In aspects, the surfactant comprises lecithin and lecithinderivatives including pure phospholipids such as, e.g., soyaphosphatidyl choline) and mixed phospholipids, sodium cholate, andhydroxylated phospholipids/hydroxylated lecithin; glycerol fatty acidesters including polyglycerol fatty acid esters, polyglycerolpolyricinoleate, hydrogenated castor oils and propylene glycol fattyacid esters (such as, e.g., polyoxyethyleneglycerol triricinoleate,Cremophor® EL (macrogol-1500-glyceroltriricinoleate), Cremophor® RH-40,and monobutyl glycerol); polysorbates such as polysorbate-80; sorbitanfatty acid esters including sorbitan monolaurate and sorbitan monoleate;polyoxyethylene sorbitan fatty acid esters including polyethylene glycolsorbitan monolaurate and polyethylene glycol sorbitan monooleate; etc.,including propylene glycol, PEGs (e.g., PEG 200), and cosurfactants suchas alkanols (e.g., ethanol, propanol, butanol, etc.), alkane-diols(e.g., 1,2-propane diol, 1,2-butane diol, etc.), and alkane-polyols(glycerol, glucitol, polyethylene glycol, etc.), or derivatives thereofor combinations of any two or more of such compounds.

Non-Irritating Nature

In aspects, compositions provided by the invention are characterized asnon-irritating. In aspects, compositions provided by the invention donot cause detectable or significant irritation in the majority of usersof the composition. In aspects, irritation is not reported as acomposition-associated adverse event in a population of test subjectsor, in aspects, a detectable or significant amount of irritation isreported by no more than about 10%, e.g., by no more than ≤˜9%, ≤˜8%,≤˜7%, ≤˜6%, ≤˜5%, ≤˜4%, ≤˜3%, ≤˜2%, ≤˜1%, ≤˜0.5%, or, e.g., ≤˜0.1%, of apopulation of subjects in an appropriately conducted and controlledclinical trial. In aspects, compositions provided by the inventionprovide detectably or significantly less irritation (e.g., the level ofirritation reported by a user is detectably or significantly less), lessfrequent irritation, or both using composition(s) herein compared tocompositions comprising one or more non-ionicpolyoxyethylene-polyoxypropylene block copolymers. In aspects,compositions provided by the invention provide detectably orsignificantly less irritation (e.g., the level of irritation reported bya user is detectably or significantly less), less frequent irritation,or both using composition(s) herein compared to similar compositionscomprising one or more non-ionic polyoxyethylene-polyoxypropylene blockcopolymers wherein the non-ionic polyoxyethylene-polyoxypropylene blockcopolymer has the chemical structureHO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein x is an integer havingthe value of at least 8 and y is an integer having the value of at least38 as the suspension agent.

Viscosity

In aspects, compositions provided by the invention have a viscositysuitable for via injection, such as, e.g., via intracameral injection.In aspects, compositions comprise viscosity and suspensioncharacteristics such that the composition can be effectivelyadministered through a needle having a gauge size of about 25 or higher,such as a needle having a gauge size of ˜26, ˜27, ˜28, ˜29, ˜30, ˜31,˜32, ˜33, or, e.g., ˜34. In aspects, compositions herein can beadministered without failure (such as, e.g., by clogging of the needledue to particulate agglomeration) at least 90%, ≥˜92%, ≥˜94%, ≥˜96%,≥˜98%, ≥˜99%, or, e.g., even 100% of the time through a needle having agauge size of 27. In aspects, compositions herein can be administeredwithout failure (such as, e.g., by clogging of the needle due toparticulate agglomeration) at least 90%, ≥˜92%, ≥˜94%, ≥˜96%, ≥˜98%,≥˜99%, or, e.g., even 100% of the time without failure through a needlehaving a gauge size of 28. In aspects, compositions herein can beadministered without failure (such as, e.g., by clogging of the needledue to particulate agglomeration) at least 90%, ≥˜92%, ≥˜94%, ≥˜96%,≥˜98%, ≥˜99%, or, e.g., even 100% of the time through a needle having agauge size of 29. In aspects, administration of the compositionscomprises shaking the compositions prior to use, such as, e.g., shakingby hand for at least about 5 seconds, such as, at least 6, ˜7, ˜8, ˜9,or, e.g., ˜10 seconds. In aspects, any significant flocculation whichhas occurred during shipping, storage, or at any period aftermanufacturing and prior to administration is resolved, and compositionscan be administered without failure (such as, e.g., by clogging of theneedle due to particulate agglomeration) at least 90%, ≥˜92%, ≥˜94%,≥˜96%, ≥˜98%, ≥˜99%, or, e.g., even 100% of the time through a needlehaving a gauge size of 27, 28, or 29.

In aspects, compositions provided by the invention have a viscositywhich DOS negatively impact the intraocular pressure of the eye uponadministration by injection, such as, e.g., composition(s) do not have aviscosity which, when administered by injection into aqueous humor orintravitreal injection, DOS increases the intraocular pressure such thata negative side effect of intraocular pressure increase manifests, suchas, e.g., headache, eye pain, nausea, vomiting, blurred vision, haloformation around lights, eye redness, etc.

In aspects, compositions have a viscosity of from about 1-30 mPas, suchas, e.g., between ˜1.2-˜30, mPas, ˜1.4-˜30, mPas, ˜1.6-˜30, mPas,˜1.8-˜30, mPas, ˜2-˜30, mPas, ˜2.2-˜30, mPas, ˜2.4-˜30, mPas, ˜2.6-˜30,mPas, ˜2.8-˜30, mPas, ˜3-˜30, mPas, ˜3.2-˜30, mPas, ˜3.4-˜30, mPas, or,e.g., ˜3.6-˜30, mPas, such as, e.g., ˜1-˜28.5 mPas, ˜1-˜28 mPas,˜1-˜27.5 mPas, ˜1-˜27 mPas, ˜1-˜26.5 mPas, ˜1-˜26 mPas, ˜1-˜25.5 mPas,˜1-˜25 mPas, or, e.g., ˜1-˜24.5 mPas, as in, e.g., ˜1.5 to ˜28.5 mPas,˜2-˜27.5 mPas, ˜2.5-˜26.5 mPas, ˜3-˜25.5 mPas, ˜3.5-˜25 mPas, or, e.g.,about 3.7-24.2 mPas.

In aspects, compositions provided by the invention have a pH within arange of between about 5-about 9, such as, e.g., between ˜5-˜9.4,˜5-˜9.3, ˜5-˜9.2, ˜5-˜9.1, ˜5-˜9, ˜5-˜8.9, ˜5-˜8.8, ˜5-˜8.7, ˜5-˜8.6,or, e.g., ˜5-˜8.5, or, e.g., ˜5.1-˜9.5, or ˜5.2-˜9.5, ˜5.4-˜9.5,˜5.5-˜9.5, ˜5.6-˜9.5, ˜5.7-˜9.5, ˜5.8-˜9.5, ˜5.9-˜9.5, ˜6-˜9.5,˜6.1-˜9.5, ˜6.2-˜9.5, ˜6.3-˜9.5, ˜6.4-˜9.5, or, e.g., ˜6.5-˜9.5, suchas, e.g., ˜5.7-˜9.2, ˜6-˜8.9, ˜6.1-˜8.8, ˜6.2-˜8.7, ˜6.3-˜8.6,˜6.4-˜8.6, or, e.g., ˜6.5-˜8.5, such as between about 6.6-about 8.2,˜6.7-˜8, ˜6.8-˜7.8, ˜6.8-˜7.6, ˜6.8-˜7.4, ˜6.8-˜7.2, or, e.g., about 7.In aspects, compositions provided by the invention are capable ofmaintaining a pH of between about 6.5-8.5 over the course of a period ofat least about 2 months, ≥˜3 months, ≥˜4 months, ≥˜5 months, ≥˜6 months,≥˜7 months, ≥˜8 months, ≥˜9 months, ≥˜10 months, ≥˜11 months, ≥˜12months, ≥˜18 months, or, e.g., ≥˜24 months after manufacturing (e.g.,while in shelf storage under directed conditions, prior to use, or,e.g., while stored at about 25° C. and about 40% relative humidity,about 40° C. and no more than about 25% relative humidity, or both(ophthalmic product), or, e.g., 25° C. and 60% relative humidity or at40° C. and 75% relative humidity for 3 months (injectable product)).

Osmolality

In aspects, compositions provided by the invention have an osmolality ofbetween about 150-400 mOsm/Kg, such as, e.g., 160-˜400 mOsm/Kg, 170-˜400mOsm/Kg, 180-˜400 mOsm/Kg, 190-˜400 mOsm/Kg, 200-˜400 mOsm/Kg, such as,e.g., ˜150-˜390 mOsm/Kg, ˜150-˜380 mOsm/Kg, ˜150-˜360 mOsm/Kg, or, e.g.,˜150-˜350 mOsm/Kg, as in between ˜210-˜380 mOsm/Kg, ˜220-˜360 mOsm/Kg,˜230-˜340 mOsm/Kg, ˜240-˜320 mOsm/Kg, ˜250-˜310 mOsm/Kg, ˜260-˜300mOsm/Kg, ˜270-˜290 mOsm/Kg, or, e.g., between ˜280-˜290 mOsm/Kg.

Stability

Compositions of the invention can be, in aspects, characterized on thebasis of physical stability, chemical stability, or both. In aspects,compositions exhibit sufficient physical and chemical integrity tomaintain at least ˜98% of the amount of any included API(s) and tomaintain total impurities below 0.5% (e.g., below pharmaceuticallyacceptable level) to allow storage at a convenient temperature, such asbetween about 2° C. and about 50° C., for a commercially reasonableperiod of time, such as, e.g., at least about 1 month, such as at leastabout 2 months, or at least about 3 months or more, e.g. typically forat least about 4, ˜5, ˜6, ˜7, ˜8, ˜9, ˜10, ˜11, ˜12, ˜18, ˜24, ˜30, or,e.g., ˜36 months, when stored in its original packaging. The term“physical stability” typically refers to maintenance of color, dissolvedoxygen level, head space oxygen level, particulate matter, etc. Relevantto suspensions, physical stability can refer to no DOS increase incoagulation, flocculation, caking, clumping, etc. In aspects, physicalstability for suspensions means no DOS flocculation, coagulation, orclumping, etc., or at least no sustained flocculation, coagulation,clumping, etc. (e.g., flocculation, coagulation, clumping, etc., that isnot reduced to below visual detection levels upon routine agitation suchas about 0.5-5, 0.3-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-1, or 0.25-2.5minutes of manual shaking). Related aspects are described elsewhereherein. The term “chemical stability” typically refers to formation ofdrug-related impurities in terms of total impurity, single maximumindividual impurity, and maximum individual unknown impurity, or to thereduction in API due to undesired reactions. For the purpose of thecompositions provided by the invention described here. In aspects,chemical stability also includes maintenance of pH of the finishedformulation.

The terms “impurity” or “impurities” refer to undesired substance(s) ina composition which may be present in a composition immediatelyfollowing manufacturing (e.g., at initial quality control testingcomposition following manufacturing, prior to storage) or which may beformed after a certain period of shelf life of a composition. Impuritiesmay be formed via degradation of one or more components of thecomposition. Sources of degradation can include, e.g., oxidation, light,ultraviolet light, moisture, heat, changes in pH, and compositioncomponent interactions.

In aspects, compositions provided by the invention are stablecompositions such that quinolone antibiotic component constituent(s) ofthe compositions, the anti-inflammatory steroid componentconstituents(s) of the compositions, or both the quinolone antibioticand anti-inflammatory API(s) are present in an amount of at least 98%,such as ≥˜98.2%, ≥˜98.4%, ≥˜98.6%, ≥˜98.8%, ≥˜99%, ≥˜99.2%, ≥˜99.4%,≥˜99.6%, ≥˜99.8%, or even ˜100% for a period of at least about 1 month(e.g., ˜2, ˜3, ˜4, ˜5, ˜6 months or more such as ≥12, ≥18, or ≥24months) when stored at relevant conditions, such as, e.g., at about 25°C. and about 40% relative humidity, at about 40° C. and not more than25% relative humidity, or both (e.g., for an ophthalmic topical/dropproduct), or, e.g., 25° C. and 60% relative humidity or at 40° C. and75% relative humidity for 3 months (e.g., for an ophthalmologicalinjectable product).

In aspects, compositions provided by the invention are capable ofmaintaining a level of total impurities of less than about 0.5%, such asless than ˜0.4%, <˜0.3%, <˜0.2%, or, e.g., <0.1% or less than thatquantifiable by the limits of detection of impurity detection equipmentused in such an analysis, for a period of at least about 1 month or,e.g., ≥˜2 months, ≥˜3, ≥˜4, ≥˜5, or ≥˜6 months or more when stored atrelevant conditions, such as FDA stability testing conditions, such as,e.g., at about 25° C. and about 40% relative humidity, at about 40° C.and not more than 25% relative humidity, or both (e.g., for anophthalmic applied product, such as an eye drop product), or, e.g., 25°C. and 60% relative humidity or at 40° C. and 75% relative humidity for3 months (for an injectable product).

In aspects, compositions herein retain at least about 85 w/w. % of thepotency, e.g., ≥˜85 w/w. %, ≥˜85 w/w. %, ≥˜86 w/w. %, ≥˜87 w/w. %, ≥˜88w/w. %, ≥˜89 w/w. %, ≥˜90 w/w. %, ≥˜91 w/w. %, ≥˜92 w/w. %, ≥˜93 w/w. %,≥˜94 w/w. %, ≥˜95 w/w. %, ≥˜96 w/w. %, ≥˜97 w/w. %, ≥˜98 w/w. %, ≥˜99w/w. %, or even, e.g., 100 w/w. % of the activity of any quinoloneantibiotic component, one or more quinolone antibiotic componentconstituents, e.g., an antibacterial compound constituent, anyanti-inflammatory steroid component, one or more anti-inflammatorysteroid component constituents, any combination of any or all thereofincluding all of such ingredients for at least about 1 month, such as,e.g., >6 weeks, >2 months, ≥˜10 weeks, ≥˜3 months, ≥˜4 months, ≥˜5months, ≥˜6 months, ≥˜7 months, ≥˜8 months, ≥˜9 months, ≥˜10 months,≥˜11 months, ≥˜12 months, ≥˜14 months, ≥˜16 months, ≥˜18 months, ≥˜20months, ≥˜22 months, ≥˜24 months, ≥˜26 months, ≥˜28 months, ≥˜30 months,≥˜32 months, ≥˜34 months, or, e.g., ≥˜36 months or more (under relevantconditions, such as those described above or elsewhere herein).

In aspects, compositions herein retain at least about 85 w/w. % of thepotency, e.g., ≥˜85 w/w. %, ≥˜85 w/w. %, ≥˜86 w/w. %, ≥˜87 w/w. %, ≥˜88w/w. %, ≥˜89 w/w. %, ≥˜90 w/w. %, ≥˜91 w/w. %, ≥˜92 w/w. %, ≥˜93 w/w. %,≥˜94 w/w. %, ≥˜95 w/w. %, ≥˜96 w/w. %, ≥˜97 w/w. %, ≥˜98 w/w. %, ≥˜99w/w. %, or even, e.g., 100 w/w. % of the activity of the labeledconcentration of moxifloxacin for at least about 1 month, such as, e.g.,≥˜6 weeks, ≥˜2 months, ≥˜10 weeks, ≥˜3 months, ≥˜4 months, ≥˜5 months,≥˜6 months, ≥˜7 months, ≥˜8 months, ≥˜9 months, ≥˜10 months, ≥˜11months, ≥˜12 months, ≥˜14 months, ≥˜16 months, ≥˜18 months, ≥˜20 months,≥˜22 months, ≥˜24 months, ≥˜26 months, ≥˜28 months, ≥˜30 months, ≥˜32months, ≥˜34 months, or, e.g., ≥˜36 months or more under storageconditions provided by the label (e.g., under typical storageconditions).

In aspects, compositions herein retain at least about 85 w/w. % of thepotency, e.g., ≥˜85 w/w. %, ≥˜85 w/w. %, ≥˜86 w/w. %, ≥˜87 w/w. %, ≥˜88w/w. %, ≥˜89 w/w. %, ≥˜90 w/w. %, ≥˜91 w/w. %, ≥˜92 w/w. %, ≥˜93 w/w. %,≥˜94 w/w. %, ≥˜95 w/w. %, ≥˜96 w/w. %, ≥˜97 w/w. %, ≥˜98 w/w. %, ≥˜99w/w. %, or even, e.g., 100 w/w. % of the activity of the labeledconcentration of gatifloxacin for at least about 1 month, such as, e.g.,≥˜6 weeks, ≥˜2 months, ≥˜10 weeks, ≥˜3 months, ≥˜4 months, ≥˜5 months,≥˜6 months, ≥˜7 months, ≥˜8 months, ≥˜9 months, ≥˜10 months, ≥˜11months, ≥˜12 months, ≥˜14 months, ≥˜16 months, ≥˜18 months, ≥˜20 months,≥˜22 months, ≥˜24 months, ≥˜26 months, ≥˜28 months, ≥˜30 months, ≥˜32months, ≥˜34 months, or, e.g., ≥˜36 months or more under storageconditions provided by the label (e.g., under typical storageconditions).

In aspects, compositions herein retain at least about 85 w/w. % of thepotency, e.g., ≥˜85 w/w. %, ≥˜85 w/w. %, ≥˜86 w/w. %, ≥˜87 w/w. %, ≥˜88w/w. %, ≥˜89 w/w. %, ≥˜90 w/w. %, ≥˜91 w/w. %, ≥˜92 w/w. %, ≥˜93 w/w. %,≥˜94 w/w. %, ≥˜95 w/w. %, ≥˜96 w/w. %, ≥˜97 w/w. %, ≥˜98 w/w. %, ≥˜99w/w. %, or even, e.g., 100 w/w. % of the activity of the labeledconcentration of triamcinolone acetonide for at least about 1 month,such as, e.g., ≥˜6 weeks, ≥˜2 months, ≥˜10 weeks, ≥˜3 months, ≥˜4months, ≥˜5 months, ≥˜6 months, ≥˜7 months, ≥˜8 months, ≥˜9 months, ≥˜10months, ≥˜11 months, ≥˜12 months, ≥˜14 months, ≥˜16 months, ≥˜18 months,≥˜20 months, ≥˜22 months, ≥˜24 months, ≥˜26 months, ≥˜28 months, ≥˜30months, ≥˜32 months, ≥˜34 months, or, e.g., ≥˜36 months or more understorage conditions provided by the label (e.g., under typical storageconditions).

In aspects, compositions herein retain at least about 85 w/w. % of thepotency, e.g., ≥˜85 w/w. %, ≥˜85 w/w. %, ≥˜86 w/w. %, ≥˜87 w/w. %, ≥˜88w/w. %, ≥˜89 w/w. %, ≥˜90 w/w. %, ≥˜91 w/w. %, ≥˜92 w/w. %, ≥˜93 w/w. %,≥˜94 w/w. %, ≥˜95 w/w. %, ≥˜96 w/w. %, ≥˜97 w/w. %, ≥˜98 w/w. %, ≥˜99w/w. %, or even, e.g., 100 w/w. % of the activity of the labeledconcentration of loteprednol etabonate for at least about 1 month, suchas, e.g., ≥˜6 weeks, 22 months, ≥˜10 weeks, ≥˜3 months, ≥˜4 months, ≥˜5months, ≥˜6 months, ≥˜7 months, ≥˜8 months, ≥˜9 months, ≥˜10 months,≥˜11 months, ≥˜12 months, ≥˜14 months, ≥˜16 months, ≥˜18 months, ≥˜20months, ≥˜22 months, ≥˜24 months, ≥˜26 months, ≥˜28 months, ≥˜30 months,≥˜32 months, ≥˜34 months, or, e.g., ≥˜36 months or more under storageconditions provided by the label (e.g., under typical storageconditions).

In aspects, compositions herein retain at least about 85 w/w. % of thepotency, e.g., ≥˜85 w/w. %, ≥˜85 w/w. %, ≥˜86 w/w. %, ≥˜87 w/w. %, ≥˜88w/w. %, ≥˜89 w/w. %, ≥˜90 w/w. %, ≥˜91 w/w. %, ≥˜92 w/w. %, ≥˜93 w/w. %,≥˜94 w/w. %, ≥˜95 w/w. %, ≥˜96 w/w. %, ≥˜97 w/w. %, ≥˜98 w/w. %, ≥˜99w/w. %, or even, e.g., 100 w/w. % of the activity of the labeledconcentration of prednisolone acetate for at least about 1 month, suchas, e.g., ≥˜6 weeks, 22 months, ≥˜10 weeks, ≥˜3 months, ≥˜4 months, ≥˜5months, ≥˜6 months, ≥˜7 months, ≥˜8 months, ≥˜9 months, ≥˜10 months,≥˜11 months, ≥˜12 months, ≥˜14 months, ≥˜16 months, ≥˜18 months, ≥˜20months, ≥˜22 months, ≥˜24 months, ≥˜26 months, ≥˜28 months, ≥˜30 months,≥˜32 months, ≥˜34 months, or, e.g., ≥˜36 months or more under storageconditions provided by the label (e.g., under typical storageconditions).

In aspects, compositions herein retain at least about 85 w/w. % of thepotency, e.g., ≥˜85 w/w. %, ≥˜85 w/w. %, ≥˜86 w/w. %, ≥˜87 w/w. %, ≥˜88w/w. %, ≥˜89 w/w. %, ≥˜90 w/w. %, ≥˜91 w/w. %, ≥˜92 w/w. %, ≥˜93 w/w. %,≥˜94 w/w. %, ≥˜95 w/w. %, ≥˜96 w/w. %, ≥˜97 w/w. %, ≥˜98 w/w. %, ≥˜99w/w. %, or even, e.g., 100 w/w. % of the activity of the labeledconcentration of bromfenac for at least about 1 month, such as, e.g.,≥˜6 weeks, ≥˜2 months, ≥˜10 weeks, ≥˜3 months, ≥˜4 months, ≥˜5 months,≥˜6 months, ≥˜7 months, ≥˜8 months, ≥˜9 months, ≥˜10 months, ≥˜1 months,≥˜12 months, ≥˜14 months, ≥˜16 months, ≥˜18 months, ≥˜20 months, ≥˜22months, ≥˜24 months, ≥˜26 months, ≥˜28 months, ≥˜30 months, ≥˜32 months,≥˜34 months, or, e.g., ≥˜36 months or more under storage conditionsprovided by the label (e.g., under typical storage conditions).

In aspects, the characterization of “stable” can be used to describe theability of compositions to effectively maintain both a quinoloneantibiotic component and an anti-inflammatory steroid component insuspension, such that the consistency of the composition is at leastgenerally, substantially, or effectively uniform, e.g., at least about90%, e.g., ≥˜91%, ≥˜92%, ≥˜93%, ≥˜94%, ≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%,≥˜99%, or, e.g., even about 100% of the composition has a relative ratioof any single component to any other single component of no more than1.1:1, such as no more than ˜1.09:1, 1.08:1, 1.07:1, 1.06:1, 1.05:1,1.04:1, 1.03:1, 1.02:1, 1.01:1 or, e.g., about 1:1.

In aspects, compositions of the invention can be characterized on thebasis of having uniformity, maintaining uniformity over time, or both.In general, composition uniformity can be described by a uniformity ofcontent equation:

${{Uniformity}\mspace{14mu}{of}\mspace{14mu}{content}} = {\frac{{Detected}\mspace{20mu}{content}}{{Theoretical}\mspace{14mu}{content}} \times 100}$In the provided equation, “detected content” is the amount orconcentration of compound detected in a sample; “theoretical content” isthe amount or concentration of compound which should be present in acompletely uniform composition. In aspects, when at least 10 samples ofa well-mixed (e.g., well-shaken, such as, e.g., shaken by hand for atleast about 5 seconds) are tested for any given active ingredient (e.g.,a fluoroquinolone antibiotic compound, a steroid anti-inflammatorycompound, or, e.g., a non-steroid anti-inflammatory compound) at least90% of all samples result in a uniformity of content between 85%-115%.In aspects, when at least about 90%, ˜92%, ˜94%, ˜96%, ˜98%, or moresamples tested have a uniformity of content between about 90% and 120%,90% and 115%, or, e.g., between about 90% and 110%.

In aspects, conducting the above content uniformity analysis on 10 ormore samples each having been stored for, e.g., 1 month (e.g., ˜2, ˜3,˜4, ˜5, ˜6 months or more such as ≥12, ≥18, or ≥24 months) when at about25° C. and about 40% relative humidity, at about 40° C. and not morethan 25% relative humidity, or both (ophthalmic product), or, e.g., 25°C. and 60% relative humidity or at 40° C. and 75% relative humidity for3 months (injectable product) results in at least about 90% of suchsamples having a content uniformity meeting USP acceptability criteriafor ophthalmic suspensions.

In aspects, when 10 or more samples, such as, e.g., ≥˜12, ≥˜14, ≥˜16,≥˜18, or, e.g., ≥˜20 or more samples of a single manufactured batch ofophthalmic composition are tested using the above method, at least about85%, ˜90%, ˜95%, or more, such as 100% of samples have a contentuniformity meeting USP acceptability criterion for ophthalmicsuspensions. In aspects, when ˜3, 4, ˜5, 6, ˜7, ˜8, ˜9, or, e.g., ˜10 ormore samples, such as, e.g., ≥˜12, ≥˜14, ≥˜16, ≥˜18, or, e.g., ≥˜20 ormore doses of a treatment regimen of ophthalmic composition are testedusing the above method, at least about 85%, ˜90%, ˜95%, or more, such as100% of such samples have a content uniformity meeting USP acceptabilitycriteria for ophthalmic suspensions.

In aspects, content uniformity can be described by comparing the amountof any given active ingredient received in one dose with the amount ofthe same active ingredient received in any subsequent dose. In aspects,across a treatment period (of, e.g., about 1 day, ˜2 days, ˜3 days, ˜4,days, ˜5 days, ˜6 days, ˜7 days, ˜8 days, ˜9 days, or, e.g., ˜10 days),the amount of any given active ingredient received in one dose is notless than 85% of, and not more than 120% more than, the amount of thesame active ingredient received in any other dose of the treatmentperiod.

Route of Administration

In aspects, the invention provides compositions which are administeredby injection. In aspects, compositions provided by the invention areadministered by intracameral injection. In aspects, the inventionprovides compositions which are administered topically, such as, e.g.,as drops. In aspects, compositions are provided in ready-to-use form,such as, e.g., prepackaged in injection device(s) or prepackaged indropper bottle(s) as is described elsewhere herein.

Method of Making/Manufacturing Compositions

In aspects, the invention provides methods of manufacturing acomposition described herein. In aspects, the invention provides methodsof manufacturing a composition comprising ophthalmologically suitableamounts of (1) one or more quinolone antibiotic components (e.g., one ormore antibacterial compounds), (2) one or more anti-inflammatory steroidcomponents (e.g., one or more steroid compounds such as a corticosteroidcompounds, one or more non-steroid compounds, or a combination thereof),(3) one or more suspension agents (such as, e.g., hyaluronic acid), andoptionally (4) one or more excipients or additional APIs, such as, e.g.,an effective amount of chelating agent(s) such as an EDTA compound, aneffective amount of surfactant(s), an effective amount ofviscoelasticity agent(s), an effective amount of preservative(s),buffer(s), emulsifier(s), or sequestration agent(s), including anyderivative thereof, or combination of any or all thereof). In aspects,such a composition has pH of between about 6.5-about 8.5, is stable forat least 1 month when stored at ˜25° C. and ˜40% relative humidity or atabout 40° C. and no more than about 25% relative humidity (ophthalmicproduct), or, e.g., 25° C. and 60% relative humidity or at 40° C. and75% relative humidity for 3 months (injectable product), and maintains atotal level of impurities of less than ˜0.5% for a period of at leastabout 1 month (e.g., ≥3, ≥6, ≥12, ≥18, or ≥24 months) when stored atabout 25° C. and about 40% relative humidity, at about 40° C. and notmore than 25% relative humidity, or both (ophthalmic product) or 25° C.and 60% relative humidity or at 40° C. and 75% relative humidity for 3months (injectable product).

In aspects, compositions provided by the invention are prepared (e.g.,are manufactured) according to any suitable technique, many of which areknown to those skilled in the art. In aspects, steps of a method ofmanufacturing can be performed in different orders.

In exemplary aspects, the manufacturing of compositions can be brokendown into 3 main parts. Part I involves forming a solution of theanti-inflammatory steroid component, Part II involves forming a solutionof all other ingredients, and Part III involves combining Parts I and IIinto a final solution.

Part I.

In aspects, the method of manufacturing comprises adding the totalquantity of anti-inflammatory agent and, in a suitable container, tototal a volume of water (e.g., water for injection (WFI) which is lessthan the ultimate final total volume of the composition batch, such as,e.g., a total volume representing about 20, ˜25%, ˜30%, ˜35%, or ˜40% ofthe total volume. In aspects, a suspension is created. In aspects, theanti-inflammatory agent is, e.g., triamcinolone, prednisolone, or, e.g.,loteprednol.

In such aspects, the suspension is treated to form a suspension whereinparticles of the suspension have a targeted particle size. In aspects,the suspension is treated by any method known in the art for formingparticular particle sizes, such as homogenization. In aspects, thesuspension is then passed through a homogenizer. In aspects, theresulting suspension, after homogenization, comprises particles having aD₅₀ of greater than about 0.25 μm but less than about 3.75 μm, such asbetween ˜0.25-˜3.5 μm, ˜0.25-˜3.25 μm, ˜0.25-˜3 μm, ˜0.25-˜2.75 μm,˜0.25-˜2.5 μm, ˜0.25-˜2 μm, ˜0.25-˜1.75 μm, or, e.g., ˜0.25-˜1.5 μm,such as, e.g., ˜0.5-˜3.75, ˜0.75-˜3.75 μm, ˜1-˜3.75 μm, ˜1.25-˜3.75 μm,˜1.5-˜3.75 μm, ˜1.75-˜3.75 μm, or, e.g., between ˜2-˜3.75 μm, such as,e.g., between about 0.5-1.5 μm, ˜2-˜3 μm, or, e.g., between ˜0.5-3 m.

In such aspects, upon completion of homogenization, the composition issterilized. In aspects, any sterilization method known in the art can beused for sterilizing the suspension. In aspects, the suspension issterilized using an autoclave. In aspects, the suspension is autoclavedat between about 115° C.-135° C. for up to 1 hour. For example, thesuspension is autoclaved at 121° C. for about 20-about 40 minutes, suchas, e.g., ˜25 minutes, ˜30 minutes, ˜35 minutes, or, e.g., ˜40 minutes.In aspects, the suspension is autoclaved for a sufficient amount of timeand at a sufficient temperature to sterilize the composition by thermallethalization without negatively impacting any one or more ingredients,such as e.g., causing DOS degradation of any one or more ingredientsincluding a reduction in a DOS amount of any one or more ingredients ora DOS in an amount of activity which an ingredient can impart either tothe composition or therapeutically upon administration. In aspects, thesterilization step detectably or significantly reduces the amount(s) ofrelated compound(s) and impurities associated with the ophthalmiccomposition upon storage of the composition at about 25° C. and about40% relative humidity, at about 40° C. and not more than 25% relativehumidity (ophthalmic product), or, e.g., 25° C. and 60% relativehumidity or at 40° C. and 75% relative humidity for 3 months (injectableproduct), or both for a period of at least about 1 month, e.g., at least˜2, ˜3, ˜4, ˜5, or, e.g., ˜6 months or more (e.g., ≥12, ≥18, or ≥˜24months).

In such aspects, after autoclaving, the suspension is stirred whileallowed to cool to about room temperature (e.g., about 25° C.+2° C.).This suspension is referred to as “Part I.” The performance of suchsteps also can be referred to as Part I.

Part II

In aspects, a separate volume of water, e.g., WFI, is collected forpreparing the quinolone antibiotic component of the composition whichcomprises one or more additional ingredients, including the suspensioncomponent. In aspects, the separate volume represents less than all ofthe remaining total volume of the composition, such as a volume whichrepresents between about 45-60% of the total volume of the composition,such as, e.g., ˜40%, ˜45%, ˜50%, ˜55%, or, e.g., about 60% of the totalcomposition volume. In aspects, one or more ingredients representing apreservative, buffer, emulsifier, or sequestering agent, e.g., sodiumcitrate monohydrate, is completely dissolved in the water.

In aspects, upon complete dissolution of the preservative, buffer,emulsifier, or sequestering agent (e.g., sodium citrate monohydrate)ingredient(s), surfactant ingredient(s) (e.g., polysorbate-80) arecompletely dissolved in the same solution.

In aspects, upon complete dissolution of the surfactant ingredient(s),e.g., polysorbate-80, chelating agent(s) (e.g., disodium edetatedihydrate) are added to the same solution and completely dissolved. Inaspects, upon complete dissolution of the chelating agent(s), e.g.,disodium edetate dihydrate), a preservative agent(s) (e.g., benzalkoniumchloride) is added. In aspects, preservative agent(s) are added later.

At this stage of Part II, steps can vary, depending on the ingredientsused in a particular formulation.

In aspects, the suspension component is added at this stage, followed bythe addition of viscoelasticity agent(s), at which time the resultingsolution is sterilized, e.g., by autoclaving, and, following,sterilization the quinolone antibiotic component is added, with orfollowed by the addition of a preservative agent, the solution isbrought to a volume by QS, the pH is adjusted, and the suspension ofPart I and the solution of Part II of the process are combined. Here,this process is referred to as Part IIA.

In aspects, the quinolone antibiotic component is added at this stage,followed by the addition of the suspension component, at which time theresulting solution is pH adjusted, the solution is brought to a volumeby QS, and the suspension of Part I and the solution of part II of theprocess are combined. Here, this process is referred to as Part IIB.

In aspects, the quinolone antibiotic component is added at this stage,followed by the addition of the suspension component, optionallyfollowed by the addition of a viscoelasticity agent(s), whereafter theresulting solution is pH adjusted, brought to volume by QS, and thesuspension of Part I and the solution of part II of the process arecombined. Herein, this process is referred to as Part IIC.

Part IIA

In aspects, upon formation of a completely dissolved solution of thepreservative, buffer, emulsifier, or sequestering agent ingredient(s),surfactant ingredient(s), and chelating agent(s), the total quantity ofthe suspension component(s) (e.g., hyaluronic acid) is added. In certainaspects, the suspension component(s) are added after the addition of thequinolone antibiotic component(s). In aspects, upon addition, themixture is stirred or otherwise agitated (e.g., stirred at moderatespeed) until the suspension agent(s) is completely dissolved, such asfor a period of about 15 minutes, ˜30 minutes, ˜45 minutes, ˜1 hour,˜1.25 hours, ˜1.5 hours, ˜1.75 hours, ˜2 hours, ˜2.25 hours, ˜2.5 hours,˜2.75 hours, or, e.g., about 3 hours or more. In aspects, a completelydissolved solution is formed within 2 hours.

In aspects, upon the complete dissolution of the suspension component(e.g., hyaluronic acid), viscoelasticity agent(s), e.g., chondroitinsulfate, is added and allowed to completely dissolve. In aspects, thisstep is absent.

In aspects, the resulting solution is sterilized using an autoclave. Inaspects, the suspension is autoclaved at between about 115° C.-135° C.for up to 1 hour. For example, the suspension is autoclaved at 121° C.for about 20-about 40 minutes, such as, e.g., ˜25 minutes, ˜30 minutes,˜35 minutes, or, e.g., ˜40 minutes. In aspects, the suspension isautoclaved for a sufficient amount of time and at a sufficienttemperature to sterilize the composition by thermal lethalizationwithout negatively impacting any one or more ingredients, such as e.g.,causing DOS degradation of any one or more ingredients including areduction in a DOS amount of any one or more ingredients or a DOS in anamount of activity which an ingredient can impart either to thecomposition or therapeutically upon administration. In aspects, thesterilization step detectably or significantly reduces the amount(s) ofrelated compound(s) and impurities associated with the ophthalmiccomposition upon storage of the composition at about 25° C. and about40% relative humidity, at about 40° C. and not more than 25% relativehumidity, or both (ophthalmic product), or, e.g., 25° C. and 60%relative humidity or at 40° C. and 75% relative humidity for 3 months(injectable product), for a period of at least about 1 month, e.g., atleast ˜2, ˜3, ˜4, ˜5, or, e.g., ˜6 months or more (e.g., ≥12, ≥18,or >˜24 months).

In aspects, upon completion of sterilization, e.g., autoclaving, thesolution is allowed to cool to about room temperature (e.g., about 25°C.+2° C.).

In aspects, upon reaching about room temperature after autoclaving, thetotal quantity of quinolone antibiotic component is added. In aspects,the total quantity of quinolone antibiotic component is allowed tocompletely dissolve, e.g., by stirring.

In aspects, upon reaching about room temperature after autoclaving, thetotal quantity of quinolone antibiotic component is added in addition toone or more preservative ingredients, e.g., benzalkonium chloride, bothof which are allowed to completely dissolve, e.g., by stirring.

In aspects, the completely dissolved solution is brought to a finalvolume of (e.g., is “QSd” to a final volume) representing between about50-about 80% of the final total volume of the composition batch, suchas, e.g., to a final volume representing about ˜50%, ˜52%, ˜54%, ˜56%,˜58%, ˜60%, ˜62%, ˜64%, ˜66%, ˜68%, ˜70%, ˜72%, ˜74%, ˜76%, ˜78%, or,e.g., ˜80%, of the total volume of the composition batch. In aspects,the solution is QS to about 65% of the final total volume.

In aspects, the pH of the solution is adjusted to between about6.5-about 8.5, such as, e.g., to ˜6.6, ˜6.7, ˜6.8, ˜6.9, ˜7, ˜7.1, ˜7.2,˜7.3, ˜7.4, ˜7.5, ˜7.6, ˜7.7, ˜7.8, ˜7.9, ˜8, ˜8.1, ˜8.2, ˜8.3, ˜8.4,or, e.g., ˜8.5, such as, e.g., to about 7.0±0.2 using pH adjustingagents. In aspects, any appropriate pH adjusting agent is used. Inaspects, the pH adjusting agent is hydrochloric acid or sodiumhydroxide.

In aspects, the Part IIA composition (above) is then sterile filteredusing a filter no bigger than 0.2 μm, e.g., using a 0.2 μm filter, intothe Part I composition (above) (Part III). In aspects, the sterilizationstep detectably or significantly reduces the amount(s) of relatedcompound(s) and impurities associated with the ophthalmic compositionupon storage of the composition at about 25° C. and about 40% relativehumidity, at about 40° C. and not more than 25% relative humidity, orboth (ophthalmic product), or, e.g., 25° C. and 60% relative humidity orat 40° C. and 75% relative humidity for 3 months (injectable product),for a period of at least about 1 month, e.g., at least ˜2, ˜3, ˜4, ˜5,or, e.g., ˜6 months or more (e.g., ≥12, ≥18, or ≥˜24 months).

An amount of water representing part or all of the remaining totalvolume of the solution is used to rinse the container of Part IIA and isthen passed through the same sterilizing filter as the previous step.

The final product is then QS to the final total batch volume by sterilefiltered water (WFI) as needed.

Part IIB

In aspects, upon formation of a completely dissolved solution of thepreservative, buffer, emulsifier, or sequestering agent ingredient(s),surfactant ingredient(s), and chelating agent(s), the total amount ofquinolone antibiotic component is added to the solution and allowed tocompletely dissolve.

In aspects, following the complete dissolution of the antimicrobialagent, the total quantity of the suspension agent(s), e.g., PEG 3350 orCMC, is added. In aspects, upon addition, the mixture is stirred orotherwise agitated (e.g., stirred at moderate speed) until thesuspension agent(s) is completely dissolved, such as for a period ofabout 15 minutes, ˜30 minutes, ˜45 minutes, ˜1 hour, ˜1.25 hours, ˜1.5hours, ˜1.75 hours, ˜2 hours, ˜2.25 hours, ˜2.5 hours, ˜2.75 hours, or,e.g., about 3 hours or more. In aspects, a completely dissolved solutionis formed within 2 hours.

In aspects, the pH of the solution is adjusted to between about6.5-about 8.5, such as, e.g., to ˜6.6, ˜6.7, ˜6.8, ˜6.9, ˜7, ˜7.1, ˜7.2,˜7.3, ˜7.4, ˜7.5, ˜7.6, ˜7.7, ˜7.8, ˜7.9, ˜8, ˜8.1, ˜8.2, ˜8.3, ˜8.4,or, e.g., ˜8.5, such as, e.g., to about 7.0±0.2 using pH adjustingagents. In aspects, any appropriate pH adjusting agent is used. Inaspects, the pH adjusting agent is hydrochloric acid or sodiumhydroxide.

In aspects, the completely dissolved solution is brought to a finalvolume of (e.g., is “QSd” to a final volume) representing between about50-about 80% of the final total volume of the composition batch, suchas, e.g., to a final volume representing about ˜50%, ˜52%, ˜54%, ˜56%,˜58%, 60%, 62%, 64%, 66%, 68%, ˜70%, ˜72%, ˜74%, ˜76%, ˜78%, or, e.g.,˜80%, of the total volume of the composition batch. In aspects, thesolution is QS to about 65% of the final total volume.

In aspects, Part IIB (above) is then sterile filtered using a filter nobigger than 0.2 μm, e.g., using a 0.2 μm filter, into Part I (above)(Part III). In aspects, the sterilization step detectably orsignificantly reduces the amount(s) of related compound(s) andimpurities associated with the ophthalmic composition upon storage ofthe composition at about 25° C. and about 40% relative humidity, atabout 40° C. and not more than 25% relative humidity, or both(ophthalmic product), or, e.g., 25° C. and 60% relative humidity or at40° C. and 75% relative humidity for 3 months (injectable product), fora period of at least about 1 month, e.g., at least ˜2, ˜3, ˜4, ˜5, or,e.g., ˜6 months or more (e.g., ≥12, ≥18, or ≥˜24 months).

An amount of water representing part or all of the remaining totalvolume of the solution is used to rinse the container of Part IIB and isthen passed through the same sterilizing filter as the previous step.

The final product is then QS to the final total batch volume by sterilefiltered water (WFI) as needed.

The manufacturing process for various formulations is furtherexemplified in the Examples section herein.

In aspects, the resulting compositions are used to fill final productcontainers, e.g., vials, dropper bottles, and the like, in preparationfor shipment, storage, or final use. In aspects, final productcontainers are containers accessible by a needle, such that a needle canbe used to extract compositions from the container for use inintracameral injection techniques, such containers and such withdrawaltechniques being known in the art.

Part IIC

In aspects, upon formation of a completely dissolved solution of thepreservative, buffer, emulsifier, or sequestering agent ingredient(s),surfactant ingredient(s), and chelating agent(s), and, optionally,preservative(s), the total amount of quinolone antibiotic component isadded to the solution and allowed to completely dissolve.

In aspects, following the complete dissolution of the antimicrobialagent, the total quantity of the suspension component, e.g., PEG 3350,CMC, or HA is added. In aspects, upon addition, the mixture is stirredor otherwise agitated (e.g., stirred at moderate speed) until thesuspension agent(s) is completely dissolved, such as for a period ofabout 15 minutes, ˜30 minutes, ˜45 minutes, ˜1 hour, ˜1.25 hours, ˜1.5hours, ˜1.75 hours, ˜2 hours, ˜2.25 hours, ˜2.5 hours, ˜2.75 hours, or,e.g., about 3 hours or more. In aspects, a completely dissolved solutionis formed within 2 hours.

In aspects, upon dissolution of the suspension component, aviscoelasticity agent, e.g., chondroitin sulfate, is added and allowedto completely dissolve.

In aspects, the pH of the solution is adjusted to between about6.5-about 8.5, such as, e.g., to ˜6.6, ˜6.7, ˜6.8, ˜6.9, ˜7, ˜7.1, ˜7.2,˜7.3, ˜7.4, ˜7.5, ˜7.6, ˜7.7, ˜7.8, ˜7.9, ˜8, ˜8.1, ˜8.2, ˜8.3, ˜8.4,or, e.g., ˜8.5, such as, e.g., to about 7.0±0.2 using pH adjustingagents. In aspects, any appropriate pH adjusting agent is used. Inaspects, the pH adjusting agent is hydrochloric acid or sodiumhydroxide.

In aspects, the completely dissolved solution is brought to a finalvolume of (e.g., is “QSd” to a final volume representing between about50-about 80% of the final total volume of the composition batch, suchas, e.g., to a final volume representing about ˜50%, ˜52%, ˜54%, ˜56%,˜58%, 60%, 62%, 64%, 66%, 68%, ˜70%, ˜72%, ˜74%, ˜76%, ˜78%, or, e.g.,˜80%, of the total volume of the composition batch. In aspects, thesolution is QS to about 65% of the final total volume.

In aspects, the composition of Part IIC (above) is then sterile filteredusing a filter no bigger than 0.2 μm, e.g., using a 0.2 μm filter, intoPart I (above) (Part III). In aspects, the sterilization step detectablyor significantly reduces the amount(s) of related compound(s) andimpurities associated with the ophthalmic composition upon storage ofthe composition at about 25° C. and about 40% relative humidity, atabout 40° C. and not more than 25% relative humidity, or both(ophthalmic product), or, e.g., 25° C. and 60% relative humidity or at40° C. and 75% relative humidity for 3 months (injectable product), fora period of at least about 1 month, e.g., at least ˜2, ˜3, ˜4, ˜5, or,e.g., ˜6 months or more (e.g., ≥12, ≥18, or ≥˜24 months).

An amount of water representing part or all of the remaining totalvolume of the solution is used to rinse the container of Part IIC and isthen passed through the same sterilizing filter as the previous step.

The final product is then QS to the final total batch volume by sterilefiltered water (WFI) as needed.

The manufacturing process for various formulations is furtherexemplified in the Examples section herein.

In aspects, the resulting compositions are used to fill final productcontainers, e.g., vials, dropper bottles, and the like, in preparationfor shipment, storage, or final use.

Product by Process Aspects

According to aspects, the invention provides an ophthalmologicallysuitable composition such as any one or more of the compositionsdescribed in this disclosure, wherein the composition is made by anyprocess of manufacturing described herein or any suitable combination ofstep(s) described in connection with such methods. The properties ofsuch compositions imparted by such steps can comprise thecharacteristics described above in connection with characteristics ofcompositions, such as physical stability of the composition.

Packaging

According to certain embodiments, ophthalmologically suitablecompositions of the invention can be packaged in any suitable packaging,such suitability being at least in part defined by protecting thecompositions held therein from degradation, contamination, or both. Incertain aspects, suitable packaging materials are materials whichexhibit less than about 20%, such as <˜18%, <˜16%, <˜14%, <˜12%, <˜10%,<˜8%, <˜6%, <˜4%, <˜2% or even less sorption of an antibiotic componentconstituent, such as, e.g., a quinolone antibiotic, or more specificallya fluoroquinolone antibiotic, such as, e.g., moxifloxacin orgatifloxacin, or an anti-inflammatory steroid component constituent,such as, e.g., a steroid or non-steroid anti-inflammatory compound. Insome respects, suitable materials include but may not be limited topackaging material made of select polyolefins, such as, e.g., DuPont® 20LDPE, Chevron 5502 HDPE, Atofina 3020 PP, polypropylene homopolymers,low ethylene content (<8%) polypropylenes, and polymers (HDPE, PP) withlow content of additives (<5%) and with low flexural modulus (<200kpsi). In some respects, a suitable material is an EP-quality LDPEwhich, in further aspects, may contain no additives. In aspects,suitable packaging can comprise a polypropylene container provided thatthat polypropylene container is not packaged in a bag/containercontaining an iron oxide oxygen scavenger.

In certain aspects, the packaging can comprise or can be mostlycomprised of (e.g., comprise in an amount ≥˜10%, ≥˜20%, ≥˜30%, ≥˜40%, or≥˜50%, such as, e.g., comprise in an amount ≥˜60%, ≥˜70%, ≥˜80%, ≥˜90%or more) an ultraviolet-light blocking agent or material. In aspects,such a material can be capable of blocking ≥˜1%, ≥˜5%, ≥˜10%, ≥˜20%,≥˜30%, ≥˜40%, or ≥˜50%, such as, e.g., ≥˜60%, ≥˜70%, ≥˜80%, ≥˜90% ormore of the ultraviolet light in the environment from entering thecontainer. In aspects, compositions described herein can be packaged in,stored, in, or both packaged and stored in a container wherein thecontainer significantly reduces exposure of the composition to UV Bradiation, such as by at least about 50%, at least about 65%, at leastabout 75%, at least about 90%, at least about 95%, or at least 99%. Insome aspect the packaging material of a composition described herein issemi- or completely opaque, while in alternative aspects, the packagingis semi- or completely clear. In aspects, packaging can comprisedifferent parts wherein one component of the packaging comprises a firstmaterial and one or more components of the packaging contain a second(or more) material(s).

In certain aspects, packaging can be selected based on the method ofdelivery of the compositions herein (e.g., compositions provided as acream can be provided in suitable packaging for creams whereincompositions provided as a liquid can be provided in suitable packagingfor liquids, e.g., in a user-friendly dropper bottle.) In aspects, thecompositions provided by the invention are stored in vials capable ofbeing penetrated by a needle such that compositions can be extractedfrom such vials and administered by injection. In aspects, compositionsare provided in pre-filled injection devices, such as, e.g., pre-filledsyringes. In aspects, the compositions of the invention are stored in apackaging that facilitates the delivery of the composition as eye drops.

In one aspect, the ophthalmic compositions comprise antimicrobialcompounds, such as, e.g., quinolone antibiotics, e.g., specificallyfluoroquinolone antibiotics such as, e.g., moxifloxacin or gatifloxacin,anti-inflammatory compound(s), such as, e.g., corticosteroid ornon-steroid compounds, and one or more pharmaceutically acceptableexcipient(s), and are provided in single-dose bottles. In an alternativeaspect, such compositions are provided in multi-dose bottles, such asmulti-dose eye dropper bottles. In aspects, such multi-dose bottlesallow for the composition, e.g., provided as a solution to be droppedinto the recipient's eye(s), to be applied as liquid drops over a courseof treatment, such as, e.g., over the course of many days, severalweeks, or longer.

In aspects, the average force required to release one or more drops ofthe compositions described herein from a dropper bottle (a standardbottle common in the art for dispensing liquid in droplet form), bycompressing the middle section of the storage body of such a dropperbottle, ranges between about 1.7-2.8 kg for release of the first drop,e.g., between about 1.7-2.6, ˜1.7-2.4, ˜1.7-2.2, or between about˜1.7-2.0. In aspects, successive drops can require more tension, such ascan require an additional ˜20-30% of force for release of the seconddrop, and, e.g., an additional force of ˜24-50% for release of the thirddrop.

In some aspects, compositions provided by the invention are administeredby intracameral injection. In aspects, compositions are provided inpackaging which is accessible via a needle such that compositions can bewithdrawn by a needle in preparation for intracameral injection. Inaspects, compositions are provided in pre-filled injection devices, suchas pre-filled syringes. In aspects, one or more pre-filled syringes areprovided in a kit as is described further elsewhere herein. In aspects,injection devices can comprise between about 0.25 mL-about 5 mL ofcomposition, though typically up to about 1 mL, such as, e.g., between˜0.5-˜5 mL, ˜0.75-˜5 mL, ˜1-˜5 mL, ˜1.25-˜5 mL, ˜1.5-˜5 mL, ˜1.75-˜5 mL,˜2-˜5 mL, ˜2.25-˜5 mL, ˜2.5-˜5 mL, ˜2.75-˜5 mL, ˜3-˜5 mL, ˜3.25-˜5 mL,˜3.5-˜5 mL, ˜3.75-˜5 mL, ˜4-˜5 mL, ˜4.25-˜5 mL, ˜4.5-˜5 mL, or, e.g.,˜4.75-˜5 mL, such as for example ˜0.25-˜4.5 mL, ˜0.25-˜4 mL, ˜0.25-˜3.5,˜0.25-˜3.5 mL, ˜0.25-˜3 mL, ˜0.25-˜2.5 mL, ˜0.25-˜2 mL, ˜0.25-˜1.5 mL,or, e.g., ˜0.25-˜1 mL of composition, as in, e.g., ˜0.1 mL, ˜0.15 mL,˜0.2 mL, ˜0.25 mL, ˜0.3 mL, ˜0.35 mL, ˜0.4 mL, ˜0.45 mL, ˜0.5 mL, ˜0.55mL, ˜0.6 mL, ˜0.7 mL, ˜0.75 mL, ˜0.8 mL, ˜0.85 mL, ˜0.9 mL, or, e.g., ˜1mL.

In aspects, compositions provided by the invention are provided insingle dose or multi-dose packaging.

In aspects, a single dose package comprises a single dose of compositionwithin a single dose administration container. In aspects, a multi-dosepackage comprises a plurality of single dose administration containers.In aspects, a multi-dose package comprises a plurality of doses within asingle administration container. For example, a multi-dose package canbe, e.g., a single dropper bottle comprising sufficient volume ofcomposition to administer the composition multiple times over the courseof an administration period, such as (but certainly not limited to)administration of about 1-3×/day over a period of about 1-7 days.

In aspects, packaging of compositions is any suitable packaging whicheffectively provides compositions with a shelf life of at least about 1month, such as, e.g., ≥˜3 weeks, ≥˜4 weeks (1 month), ≥˜5 weeks, ≥˜6weeks, ≥˜7 weeks, ≥˜8 weeks (2 months), ≥˜9 weeks, ≥˜10 weeks, ≥˜11weeks, ≥˜12 weeks (3 months), ≥˜13 weeks, ≥˜14 weeks, ≥˜15 weeks, ≥˜16weeks (4 months), or more, such as ≥˜5 months, ≥˜6 months, ≥˜7 months,≥˜8 months, ≥˜9 months, ≥˜10 months, ≥˜11 months, or ≥˜12 months (1year), or even longer, such as, ≥˜18 months, ≥˜24 months (2 years), ≥˜30months, or, e.g., ≥˜36 months (3 years) or longer.

Here, the term “shelf life” refers to the amount of time the compositionis stored without loss of potency and/or loss of a suitable dissolutionprofile, such as, e.g., loss of suitable suspension of quinoloneantibiotic component constituent(s), anti-inflammatory steroid componentconstituent(s), or both. In aspects, shelf life refers to the amount oftime the compositions effectively maintain both a quinolone antibioticcomponent and an anti-inflammatory steroid component in suspension, suchthat the consistency of the composition is at least generally,substantially, or effectively uniform, e.g., at least about 90%, e.g.,≥˜91%, ≥˜92%, ≥˜93%, ≥˜94%, ≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%, ≥˜99%, or, e.g.,even about 100% of the composition has a relative ratio of any singlecomponent to any other single component of no more than 1.1:1, such asno more than ˜1.09:1, 1.08:1, 1.07:1, 1.06:1, 1.05:1, 1.04:1, 1.03:1,1.02:1, 1.01:1 or, e.g., about 1:1. In aspects, shelf life refers to aperiod of time wherein neither the quinolone antibiotic component northe anti-inflammatory steroid component lose more than about 10%, suchas, e.g., ≤˜9%, ≤˜8%, ≤˜7%, ≤˜6%, ≤˜5%, ≤˜4%, ≤˜3%, ≤˜2%, or, e.g.,≤˜1%, of the potency while in storage after manufacturing and prior touse.

“Kits” (Collections of Components)

In aspects, the invention provides kits comprising an ophthalmologicallysuitable composition according to any one or more of the compositionsprovided by aspects of the invention described herein, packaged in oneor more containers, e.g., one or more single dose or multi-dosecontainers. In aspects, a kit comprises one or more delivery devices foradministering the composition to a recipient. In aspects, kits compriseone or more container means, which can include containers describedelsewhere (e.g., pharmaceutically acceptable vials) or known equivalentsthereof.

In aspects, the invention provides a kit comprising a delivery device asdescribed in this section, wherein any single use container comprising acomposition present in the kit is accessible to the deliverydevice/system of the kit, such as, e.g., containing a stopper whicheffectively seals the single use container and effectively preventscontamination of the content therein prior to use but which ispenetrable by the delivery device/system such that the delivery devicecan extract the composition from the single use container. In aspects,the invention provides the kit described above, wherein the deliverydevice is a syringe system, such as a syringe and an accompanying needlefor use with the syringe. In aspects, a kit can comprise “deliverymeans” including such components or known equivalents of suchcomponents.

In aspects, the invention provides a kit wherein compositions arepre-filled in a delivery device, and a kit comprises one or morepre-filled delivery devices and one or more additional components tofacilitate administration of the composition(s). For example, in aspectsthe invention provides a kit wherein compositions are pre-filled in asyringe and the kit comprises one or more needles to facilitate deliveryof the compositions by injection, such as, e.g., for administration byintracameral injection. In aspects, the invention provides a compositionwhich is formulated for injection and contained in an injection deliverydevice, a device adapted for injection delivery, or is packaged with aninjection delivery device.

In aspects, the invention provides a kit wherein composition(s) areprovided in one or more pre-filled containers which facilitateadministration of the compositions by drops, such as, e.g., one or morepre-filled dropper bottles as described herein.

In aspects, the invention provides for a kit as described in thissection, wherein the kit has a shelf life when stored at about roomtemperature, such as, e.g., about 25° C.+/−˜2° C., for at least about 1month, e.g., ˜2, ˜3, ˜4, ˜5, or at least about 6 months (e.g., 6-24mos.).

Methods of Use

In aspects, the invention provides methods of using compositionsdisclosed here in the treatment or prevention of high-risk infection.Here, “high-risk infection” refers to an infection wherein a potentiallydangerous number of bacteria is expected to be or is present in the eyeor wherein the infective agent is expected to be capable of causingdetectable or significant damage to the eye.

In aspects, compositions provided by the invention are administered inassociation with the performance of an invasive ophthalmic procedure,such as before or after an invasive ophthalmic procedure, such as anophthalmic surgery.

In aspects the invention provides methods of using compositionsdescribed herein comprising both a quinolone antibiotic component and ananti-inflammatory steroid component, wherein the anti-inflammatorysteroid component (e.g., steroidal, non-steroidal, or both) providesanti-inflammatory activity to treat or prevent inflammation associatedwith physical trauma to ophthalmic tissue(s), inflammation associatedwith microbial (e.g., bacterial) infection(s), inflammation resultingfrom surgical procedure(s), or any combination thereof.

In aspects, compositions provided by the invention are used in lieu ofother compositions comprising different active pharmaceuticalingredients to treat an ocular infection, prevent an ocular infection,treat an ocular infection-related condition or symptom such as, e.g.,inflammation, prevent an ocular infection-related condition or symptom,or any combination thereof. In aspects, compositions provided by theinvention are DOS successfully treat ocular infection and relatedconditions caused by a higher number of, e.g., broader range ofinfective agents than compositions comprising different activepharmaceutical ingredients. That is, for example, compositions providedby the invention comprising one or more quinolone antibioticseffectively treat or prevent infection or related condition(s) caused bymore infective agents than can be effectively treated or prevented byantibiotic agents such as neomycin, polymyxin B, gentamicin, ortobramycin, an exemplary group of antibiotics whose effectiveness isprimarily useful against only gram negative bacteria, or bacitracin,gramicidin, or erythromycin, an exemplary group of antibiotics whoseeffectiveness is primarily useful against only gram positive bacteria.

In aspects, methods of using compositions provided by the invention,methods treatment using compositions provided by the invention, or bothlead to DOS less frequent development of resistant bacteria which arecommonly associated with ocular infection than methods of usingalternative compositions or methods of treatment using alternativecompositions comprising alternative antimicrobial (e.g., antibiotic)agents. In aspects, methods of using compositions provided by theinvention, methods of treatment using compositions provided by theinvention, or both comprising the antimicrobial agents described herelead to a reduction in the frequency of the development of antibioticresistant infective bacteria by at least about 1%, such as, e.g., by≥˜2%, ≥˜4%, ≥˜6%, 8%, ≥˜10%, ≥˜15%, ≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%,≥˜45%, ≥˜50%, or more over compositions treating the same or similarconditions but which comprise alternative antimicrobial agents, such as,e.g., neomycin, polymyxin B, gentamicin, tobramycin, bacitracin,gramicidin, or erythromycin.

In aspects, the invention provides a method of use described in thissection, wherein any one or more of the compositions used in the methodare made according to a process/method of manufacturing provided by theinvention as described herein. In aspects, the invention provides themethod of use of the preceding paragraph wherein the method comprisesproviding the any one or more compositions for use in the method as akit provided by the invention as described herein.

In aspects, the invention provides a method of using the composition(s)described herein, wherein the composition used in the method isdelivered to the eye in a controlled manner, e.g., a drop-by-dropmanner, or, e.g., in a controlled stream of composition, such as, e.g.,the pressure and volume of composition in the stream of composition iscontrollable by the user administering the composition(s). In aspects,the invention provides a composition which is formulated for topicaladministration and is contained in a delivery device, a device adaptedfor topical delivery, or is packaged with a delivery device. In aspects,the delivery device is a dropper bottle.

In aspects, the invention provides a method of using the composition(s)described herein, wherein the composition used in the method isdelivered to the eye via intracameral injection. In aspects, theinvention provides a method of injecting composition(s) described hereininto the anterior chamber of a mammalian eye to treat an ocularinfection, to prevent an ocular infection in a patient at risk ofdeveloping an infection, to treat a condition related to an ocularinfection such as inflammation, or to prevent inflammation in a patientat risk of developing inflammation related to an ophthalmic procedure,such as an invasive ophthalmic procedure, e.g., an ophthalmic-relatedsurgery. In aspects, the invention provides a composition which isformulated for injection and contained in an injection delivery device,a device adapted for injection delivery, or is packaged with aninjection delivery device.

In aspects, compositions are provided in single dose packaging, andmethods of using compositions comprise use of compositions as providedin single dose packaging, such as, e.g., methods comprise theadministration of at least one dose of a composition per treatmentperiod. In aspects, compositions are provided in multi-dose packaging,and methods of using compositions comprise use of compositions asprovided in multi-dose packaging, such as, e.g., methods comprise theadministration of ≥1 dose of a composition per treatment period.

In aspects, the invention provides methods of using compositionsdescribed herein over the course of a treatment period of at least about1 day, such as, e.g., ≥˜2 days, ≥˜3 days, ≥˜4 days, ≥˜5 days, ≥˜6 days,≥˜7 days, ≥˜8 days, ≥˜9 days, ≥˜11 days, >12 days, ≥˜13 days, or, e.g.,≥˜14 days or longer. In aspects, the invention provides methods of usingcompositions described herein over the course of such treatment periodswherein compositions are administered about once per day, such as˜2×/day, ˜3×/day, or ˜4×/day, as in ˜1-4 times/day, ˜1-3 times/day, or,e.g., ˜1-2 times/day.

In aspects, multi-dose packaging facilitates the ease of use when morethan one dose is expected to be used over the course of anadministration period.

Methods of Treatment

In aspects, compositions provided by the invention are used to treatocular infections, such as, e.g., ocular bacterial infection(s), andrelated conditions or symptoms, such as, e.g., inflammation.Accordingly, in aspects, the invention provides methods of treatingocular infection, related conditions or symptoms, or both.

In aspects, compositions provided by the invention are used to treatbacterial conjunctivitis. In aspects, the invention provides a method oftreating bacterial conjunctivitis with composition(s) described here. Inaspects, compositions provided by the invention are used to treatbacterial conjunctivitis. In aspects, the bacterial conjunctivitis iscaused by a Streptococcus sp. infection, such as Streptococcuspneumoniae. In aspects, the bacterial conjunctivitis is caused by aHaemophilus sp. infection, such as Haemophilus influenzae. In aspects,compositions provided by the invention DOS inhibit growth of ≥1 bacteria(i.e., ≥1 bacterial species) causing an ocular bacterial infection. Inaspects, such methods DOS reduce infection-associated symptoms such as,e.g., pain, discomfort, itching, redness, swelling, discharge, reducedvision, etc. In aspects, compositions provided by the invention inhibitgrowth of a bacteria causing an active, ocular bacterial infection by atleast about 1%, such as, e.g., by ≥˜2%, ≥˜4%, ≥˜6%, 8%, ≥˜10%, ≥˜15%,≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%, ≥˜60%, ≥˜65%,≥˜70%, ≥˜75%, ≥˜80%, ≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%, ≥˜99%,or, e.g., even 100% (effectively resolving the infection).

In aspects, compositions provided by the invention are used to treat oneor more symptoms of an ocular infection. In aspects, the inventionprovides a method of treating one or more symptoms of an ocularinfection with composition(s) described here. In aspects, the infectionarises after an ophthalmological procedure, such as, e.g., an invasivesurgical procedure. In aspects, compositions provided by the inventionDOS reduce one or more symptoms of an ocular infection such as pain,discomfort, itching, redness, swelling, discharge, and reduced vision.

In aspects, compositions provided by the invention reduce the level ofpain associated with an ocular infection by a DOS amount or, in aspects,by at least about 1%, such as, e.g., by ≥˜2%, ≥˜4%, ≥˜6%, ≥˜8%, ≥˜10%,≥˜5%, ≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%, ≥˜60%,≥˜65%, ≥˜70%, ≥˜75%, ≥˜80%, ≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%,≥˜99%, or, e.g., even 100% (effectively resolving the itching) withinless than 1 week, such as, e.g., within ≤˜6 days, ≤˜5 days, ≤˜4 days,≤˜3 days, ≤˜2 days, or, e.g., ≤˜24 hours, such as ≤˜12 hours, ≤˜6 hours,or even less as reported by the average patient when measured in apopulation of patients in an appropriately conducted and poweredclinical trial. Measurement of pain can be performed using any suitablemethod(s), such as FDA approved pain measurement scales and the like.

In aspects, compositions provided by the invention reduce the level ofdiscomfort associated with an ocular infection by a DOS amount or, inaspects, by at least about 1%, such as, e.g., by ≥˜2%, ≥˜4%, ≥˜6%, ≥˜8%,≥˜10%, ≥˜5%, ≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%,≥˜60%, ≥˜65%, ≥˜70%, ≥˜75%, ≥˜80%, ≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%,≥˜98%, ≥˜99%, or, e.g., even 100% (effectively resolving the itching)within less than 1 week, such as, e.g., within ≤˜6 days, ≤˜5 days, ≤˜4days, ≤˜3 days, ≤˜2 days, or, e.g., ≤˜24 hours, such as ≤˜12 hours, ≤˜6hours, or even less as reported by the average patient when measured ina population of patients in an appropriately conducted and poweredclinical (one or more studies characterizable as adequate andwell-controlled clinical trial(s) under applicable FDA standards).

In aspects, compositions provided by the invention reduce the amount ofitching associated with an ocular infection by a DOS amount or, inaspects, by at least about 1%, such as, e.g., by ≥˜2%, ≥˜4%, ≥˜6%, ≥˜8%,≥≥˜10%, ≥≥˜5%, ≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, >≥˜45%, ≥˜50%, ≥˜55%,≥˜60%, ≥˜65%, ≥˜70%, ≥˜75%, ≥˜80%, ≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%,≥˜98%, ≥˜99%, or, e.g., even 100% (effectively resolving the itching)within less than 1 week, such as, e.g., within ≤˜6 days, ≤˜5 days, ≤˜4days, ≤˜3 days, ≤˜2 days, or, e.g., ≤˜24 hours, such as ≤˜12 hours, ≤˜6hours, or even less as reported by the average patient when measured ina population of patients in an appropriately conducted and poweredclinical trial.

In aspects, compositions provided by the invention reduce the level of,or degree of, redness associated with an ocular infection by a DOSamount or, in aspects, by at least about 1%, such as, e.g., by ≥˜2%,≥˜4%, ≥˜6%, ≥˜8%, ≥˜10%, ≥˜15%, ≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%,≥˜45%, ≥˜50%, ≥˜55%, ≥˜60%, ≥˜65%, ≥˜70%, ≥˜75%, ≥˜80%, ≥˜85%, ≥˜90%,≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%, ≥˜99%, or, e.g., even 100% (effectivelyresolving the itching) within less than 1 week, such as, e.g., within≤˜6 days, ≤˜5 days, ≤˜4 days, ≤˜3 days, ≤˜2 days, or, e.g., ≤˜24 hours,such as ≤˜12 hours, ≤˜6 hours, or even less as reported by the averagepatient or as measured by an appropriately trained clinician whenmeasured in a population of patients in an appropriately conducted andpowered clinical trial.

In aspects, compositions provided by the invention reduce the level of,or degree of, swelling associated with an ocular infection by a DOSamount or, in aspects, by at least about 1%, such as, e.g., by ≥˜2%,≥˜4%, ≥˜6%, ≥˜8%, ≥˜10%, ≥˜15%, ≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%,≥˜45%, ≥˜50%, ≥˜55%, ≥˜60%, ≥˜65%, ≥˜70%, 275%, ≥˜80%, ≥˜85%, ≥˜90%,≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%, ≥˜99%, or, e.g., even 100% (effectivelyresolving the itching) within less than 1 week, such as, e.g., within≤˜6 days, ≤˜5 days, ≤˜4 days, ≤˜3 days, ≤˜2 days, or, e.g., ≤˜24 hours,such as ≤˜12 hours, ≤˜6 hours, or even less as reported by the averagepatient or as measured by an appropriately trained clinician whenmeasured in a population of patients in an appropriately conducted andpowered clinical trial.

In aspects, compositions provided by the invention reduce the amount ofdischarge (e.g., volume of discharge) associated with an ocularinfection by a DOS amount or, in aspects, by at least about 1%, such as,e.g., by ≥˜2%, ≥˜4%, ≥˜6%, ≥˜8%, ≥˜10%, ≥˜15%, ≥˜20%, ≥˜25%, ≥˜30%,≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%, ≥˜60%, ≥˜65%, ≥˜70%, ≥˜75%, ≥˜80%,≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%, ≥˜99%, or, e.g., even 100%(effectively resolving the itching) within less than 1 week, such as,e.g., within ≤˜6 days, ≤˜5 days, ≤˜4 days, ≤˜3 days, ≤˜2 days, or, e.g.,≤˜24 hours, such as ≤˜12 hours, ≤˜6 hours, or even less as reported bythe average patient or as measured by an appropriately trained clinicianwhen measured in a population of patients in an appropriately conductedand powered clinical trial.

In aspects, compositions provided by the invention improve upon a levelof reduced vision caused by an ocular infection by a DOS amount or, inaspects, by at least about 1%, such as, e.g., by ≥˜2%, ≥˜4%, ≥˜6%, ≥˜8%,≥˜10%, ≥˜15%, ≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%,≥˜60%, ≥˜65%, ≥˜70%, 275%, ≥˜80%, ≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%,≥˜98%, ≥˜99%, or, e.g., even 100% (effectively resolving the itching)within less than 1 week, such as, e.g., within 5-6 days, ≤˜5 days, ≤˜4days, ≤˜3 days, ≤˜2 days, or, e.g., ≤˜24 hours, such as ≤˜12 hours, ≤˜6hours, or even less as reported by the average patient or measured by anappropriately trained clinician when measured in a population ofpatients in an appropriately conducted and powered clinical trial.

In aspects, compositions provided by the invention are used to, i.a.,treat or prevent inflammation related to an ocular infection, thatarises from treating an ocular infection, or both. In aspects, theinvention provides a method of treating ocular inflammation. In aspects,the invention provides a method of preventing ocular inflammationrelated to an ocular infection, ocular procedure, or both. In aspects,compositions provided by the invention, when administered before aninvasive surgical procedure, after an invasive surgical procedure, orboth DOS reduce the average percentage of patients experiencinginflammation related to the procedure. In aspects, compositions providedby the invention, when administered before an invasive surgicalprocedure, after an invasive surgical procedure, or both reduce theaverage percentage of patients experiencing inflammation related to theprocedure by ≥˜2%, ≥˜4%, ≥˜6%, ≥˜8%, ≥˜10%, ≥˜15%, ≥˜20%, ≥˜25%, ≥˜30%,≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%, ≥˜60%, ≥˜65%, ≥˜70%, ≥˜75%, ≥˜80%,≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%, ≥˜99%, or, e.g., even 100%(effectively preventing infection) over the average percentage ofpatients contracting an infection related to the same procedure who arenot prophylactically treated with composition(s) here. In aspects,compositions provided by the invention, when administered before aninvasive surgical procedure, after an invasive surgical procedure, orboth reduce the average percentage of patients experiencing inflammationrelated to an ocular infection contracted in association with theprocedure in a DOS amount or by ≥˜2%, ≥˜4%, ≥˜6%, ≥˜8%, ≥˜10%, ≥˜15%,≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%, ≥˜60%, ≥˜65%,≥˜70%, ≥˜75%, ≥˜80%, ≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%, ≥˜99%,or, e.g., even 100% (effectively preventing infection) over the averagepercentage of patients contracting an infection related to the sameprocedure who are not prophylactically treated with composition(s) here.In aspects, compositions provided by the invention reduce the level ordegree of inflammation associated with an ocular infection by a DOSamount or at least about 1%, such as, e.g., by ≥˜2%, ≥˜4%, ≥˜6%, 8%,≥˜10%, ≥˜15%, ≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%,≥˜60%, ≥˜65%, ≥˜70%, ≥˜75%, ≥˜80%, ≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%,≥˜98%, ≥˜99%, or, e.g., even 100% (effectively resolving theinflammation) within less than 1 week, such as, e.g., within ≤˜6 days,≤˜5 days, ≤˜4 days, ≤˜3 days, ≤˜2 days, or, e.g., ≤˜24 hours, such as≤˜12 hours, ≤˜6 hours, or even less as reported by the average patientor as measured by a trained clinician when measured in a population ofpatients in an appropriately conducted and powered clinical trial.

In aspects, compositions provided by the invention are usedprophylactically, e.g., to prevent an ocular infection and relatedconditions. For example, ophthalmic surgical procedures increase therisk of a patient developing an ophthalmic infection. In aspects,compositions provided by the invention are used in connection with anophthalmic surgical procedure, such as, used prophylactically inconnection with such a procedure. For example, compositions provided bythe invention are administered before an invasive surgical procedure,after an invasive surgical procedure, or both. In aspects, the inventionprovides a method of preventing an ocular infection, related condition,or both. In aspects, compositions provided by the invention, whenadministered before an invasive surgical procedure, after an invasivesurgical procedure, or both DOS reduce the average percentage ofpatients contracting an infection related to the procedure. In aspects,compositions provided by the invention, when administered before aninvasive surgical procedure, after an invasive surgical procedure, orboth reduce the average percentage of patients contracting an infectionrelated to the procedure by ≥˜2%, ≥˜4%, ≥˜6%, ≥˜8%, ≥˜10%, ≥˜15%, ≥˜20%,≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%, ≥˜60%, ≥˜65%, ≥˜70%,≥˜75%, ≥˜80%, ≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%, ≥˜99%, or, e.g.,even 100% (effectively preventing infection) over the average percentageof patients contracting an infection related to the same procedure whoare not prophylactically treated with composition(s) here.

In aspects, compositions provided by the invention are used to treat oneor more symptoms or conditions related to an ocular infection. Inaspects, compositions provided by the invention are used to treat one ormore symptoms or conditions comprising inflammation related to an ocularinfection, such conditions being conditions responsive to, and for whichappropriate or acceptable treatment can include, treatment with one ormore steroid anti-inflammatory compound(s), treatment with one or morenon-steroid anti-inflammatory compounds, or a combination thereof. Inaspects, such conditions include, e.g., conjunctivitis, keratitis,blepharitis, dacryocystitis, hordeolum and corneal ulcers. In aspects,compositions herein reduce the level of inflammation present (e.g., asmeasured by the degree of redness, degree of swelling, degree or levelof pain or discomfort associated with the inflammation) by at leastabout 1%, such as, e.g., by ≥˜2%, ≥˜4%, ≥˜6%, 8%, ≥˜10%, ≥˜15%, ≥˜20%,≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%, ≥˜60%, ≥˜65%, ≥˜70%,≥˜75%, ≥˜80%, ≥˜85%, ≥˜90%, ≥˜95%, ≥˜96%, ≥˜97%, ≥˜98%, ≥˜99%, or, e.g.,even 100% (effectively resolving the inflammation associated with thecondition) within less than 1 week, such as, e.g., within <6 days, ≤˜5days, ≤˜4 days, ≤˜3 days, ≤˜2 days, or, e.g., ≤˜24 hours, such as ≤˜12hours, ≤˜6 hours, or even less as reported by the average patient or asmeasured by a trained clinician when measured in a population ofpatients in an appropriately conducted and powered clinical trial.

In aspects, compositions herein reduce the length of time of an activeophthalmic infection, reduce the length of time one or conditionsrelated to an ophthalmic condition exist, or both by a DOS amount or atleast about 1%, such as, e.g., by ≥˜2%, ≥˜4%, ≥˜6%, ≥˜8%, ≥˜10%, ≥˜5%,≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%, ≥˜50%, ≥˜55%, ≥˜60%, ≥˜65%,≥˜70%, or, e.g., ≥˜75% or more compared to non-treatment of such acondition. In aspects, compositions herein reduce the length of time ofan active ophthalmic infection, reduce the length of time one or moreconditions related to an ophthalmic condition exist, or both by a DOSamount or at least about 1%, such as, e.g., by ≥˜2%, ≥˜4%, ≥˜5%, ≥˜6%,27%, ≥˜8%, ≥˜9%, ≥˜10%, ≥˜11%, ≥˜12%, ≥˜13%, ≥˜14%, ≥˜15%, ≥˜16%, ≥˜17%,≥˜18%, ≥˜19%, ≥˜20%, or more, such as ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%,or, e.g., ≥˜50%, or more compared to treatment using a similarcomposition comprising a non-quinolone antibiotic, a non-fluoroquinoloneantibiotic, or both.

In aspects, the invention provides a method of treating a patientsuffering from an ophthalmic infection, a condition related to anophthalmic infection (such as, e.g., inflammation), or both, comprisingapplication of a composition comprising pharmaceutically acceptableamounts of each of a quinolone antibiotic component, ananti-inflammatory steroid component, and a suspension component. Inaspects, the quinolone antibiotic component is a moxifloxacin compound,such as, e.g., moxifloxacin hydrochloride. In aspects, the antimicrobialagent is a gatifloxacin compound. In aspects, the anti-inflammatoryagent is a triamcinolone compound such as, e.g., triamcinoloneacetonide. In aspects, the anti-inflammatory agent is a prednisolonecompound, such as, e.g., prednisolone acetate. In aspects, theanti-inflammatory agent is a loteprednol compound, such as, e.g.,loteprednol etabonate. In aspects, the anti-inflammatory agent is abromfenac compound, such as bromfenac sodium sesquihydrate. In aspects,the anti-inflammatory steroid component comprises both a prednisolonecompound (e.g., prednisolone acetate) and a bromfenac compound (e.g.,bromfenac sodium sesquihydrate).

In aspects, the invention provides a method of treating a patient atrisk of developing an ophthalmic infection or inflammation, such as apatient undergoing or having completed an invasive ophthalmic procedure(e.g., an ophthalmic-related surgery), comprising application of acomposition comprising pharmaceutically acceptable amounts of each of aquinolone antibiotic component, an anti-inflammatory steroid component,and a suspension component. In aspects, the quinolone antibioticcomponent is a moxifloxacin compound, such as, e.g., moxifloxacinhydrochloride. In aspects, the antimicrobial agent is a gatifloxacincompound. In aspects, the anti-inflammatory agent is a triamcinolonecompound such as, e.g., triamcinolone acetonide. In aspects, theanti-inflammatory agent is a prednisolone compound, such as, e.g.,prednisolone acetate. In aspects, the anti-inflammatory agent is aloteprednol compound, such as, e.g., loteprednol etabonate. In aspects,the anti-inflammatory agent is a bromfenac compound, such as bromfenacsodium sesquihydrate. In aspects, the anti-inflammatory steroidcomponent comprises both a prednisolone compound (e.g., prednisoloneacetate) and a bromfenac compound (e.g., bromfenac sodiumsesquihydrate). In aspects, the composition mostly, generally only, oressentially only contains any of such referenced API(s) but can containamounts of other API(s). In aspects, the referenced API(s) is/are theprimary API(s) or essentially the only API(s) of the composition.

In aspects, the invention provides a method of treating a disease orcondition benefiting from a combination therapy of antimicrobial andanti-inflammatory compound(s), the method comprising application of acomposition comprising pharmaceutically acceptable amounts of each of aquinolone antibiotic component, an anti-inflammatory steroid component,and a suspension component. In aspects, the quinolone antibioticcomponent is a moxifloxacin compound, such as, e.g., moxifloxacinhydrochloride. In aspects, the antimicrobial agent is a gatifloxacincompound. In aspects, the anti-inflammatory agent is a triamcinolonecompound such as, e.g., triamcinolone acetonide. In aspects, theanti-inflammatory agent is a prednisolone compound, such as, e.g.,prednisolone acetate. In aspects, the anti-inflammatory agent is aloteprednol compound, such as, e.g., loteprednol etabonate. In aspects,the anti-inflammatory agent is a bromfenac compound, such as bromfenacsodium sesquihydrate. In aspects, the anti-inflammatory steroidcomponent comprises both a prednisolone compound (e.g., prednisoloneacetate) and a bromfenac compound (e.g., bromfenac sodiumsesquihydrate).

In aspects, the invention provides the methods of treatment described inthis section, wherein the compositions further comprise one or morecharacteristics described elsewhere herein, such as comprising one ormore additional excipients, one or more additional APIs, or both, suchas comprising, e.g., one or more chelating agents such as anethylenediaminetetraacetic acid (EDTA) compound (e.g., disodium edetatedihydrate) or salt thereof, one or more surfactants such aspolysorbate-80, or one or more preservative(s) (such as sodium citrate,which, in aspects, can also provide buffering, emulsifying, orsequestering activity). In aspects, such compositions can comprise oneor more carriers, such as, e.g., an aqueous carrier, e.g., WFI.

In aspects, the invention provides the methods of treatment described inthis section, wherein the method is applied a patient who has undergone,or who will receive, an ophthalmologically-related procedure/ophthalmicprocedure, such as an invasive ophthalmologically-relatedprocedure/ophthalmic procedure, which is selected from a groupcomprising cataract surgery and intraocular lens replacement.

In aspects, the invention provides the methods of treatment described inthis section, wherein any one or more of the compositions used in themethod are made according to a process or method of manufacturingdescribed herein.

In aspects, the invention provides the methods of treatment described inthis section, wherein any one or more compositions used in the methodare provided for use in the method as a component of a kit as describedherein.

In aspects, the invention provides the methods of treatment described inthis section, wherein the compositions used in the method are deliveredto the eye in a controlled manner, such as, e.g., in a drop-by-dropmanner or, e.g., in a controlled stream of composition, such as, e.g.,the pressure and volume of composition in the stream of composition iscontrollable by the user administering the composition(s).

In aspects, the invention provides the methods of treatment described inthis section, wherein the compositions used in the method are deliveredto the eye by injection, such as, e.g., by intracameral injection.

In aspects, the invention provides the methods of treatment described inthis section wherein the composition(s) are administered once, twice,three times, or four times per day for a period of about 1, ˜2, ˜3, ˜4,˜5, ˜6, or, e.g., ˜7 days.

In aspects, the invention provides the method of treatment of any one ormore of the paragraphs of this section, wherein treatment with thecomposition(s) provides detectably or significantly fewer side effectsselected from a group comprising accommodation disturbance, anterioruveitis, blepharitis, conjunctival hyperemia, conjunctivitis, cornealperforation or ulcer, decreased visual acuity, eye infection, glaucoma,increased intraocular pressure, keratitis, mydriasis, optic nervedamage, visual field defect, wound healing impairment, conjunctivalirritation, dysgeusia, eye discharge, eye irritation, eye pain, eyeredness, eyelid edema, headache, increased lacrimation, papillaryconjunctivitis, pyrexia, subconjunctival hemorrhage, tearing, abnormalsensation in eye(s), anterior chamber eye hemorrhage, burning, cornealerosion, corneal thinning, epithelial keratopathy, pruritis, iritis,prolonged bleeding, stinging, or hypersensitivity reaction thantreatment with any one or more of ImprimusRx Moxifloxacin IntraocularSolution for Injection, ImprimusRx Prednisolone Acetate Moxifloxacinophthalmic suspension, ImprimusRx Prednisolone Acetate MoxifloxacinNepafenac ophthalmic suspension, ImprimusRx Prednisolone-Bromfenacsuspension, ImprimusRx Prednisolone-Bromfenac ophthalmic drops,ImprimusRx Prednisolone Sodium Phosphate Bromfenac ophthalmic solution,ImprimusRx Prednisolone-Gatifloxacin-Bromfenac ophthalmic drops,ImprimusRx Prednisolone Acetate Moxifloxacin Bromfenac ophthalmicsuspension, and ImprimusRx Triamcinolone Acetonide Moxifloxacin HClintraocular suspension for Injection. In aspects, compositions of theinvention lack one or more of the excipients contained in suchcompositions. In aspects, compositions of the invention also oralternatively lack any one or more of the excipients described in any ofthe prior art compositions cited in the Background of the Invention(Background) section of this disclosure.

EXEMPLARY ASPECTS OF THE INVENTION

The following is a non-limiting list of exemplary aspects of theinvention.

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) a suspension component consisting of both (1) aneffective amount of least one non-ionic suspension agent and (2) aneffective amount of at least one ionic suspension agent; (b) at leasttwo pharmaceutical ingredients comprising (1) moxifloxacin in a range ofabout 0.01% to about 0.5% by weight, and (2) loteprednol in a range ofabout 0.1% to about 5% by weight, or a pharmaceutically acceptable saltsthereof; and (c) a pharmaceutically acceptable chelating agent thatresults in a significantly similar or improved stability of the activeingredients as compared to disodium edetate in a concentration of about0.1 to 0.5 mg/mL (aspect 1).

In aspects, the invention provides the composition of aspect 1, whereinthe suspension component of the composition comprises only twosuspension agents (aspect 2).

In aspects, the invention provides the composition of one or both ofaspect 1 or aspect 2, wherein the ratio of moxifloxacin to thesuspension component is from 1:10 to 1:32 (aspect 3).

In aspects, the invention provides the composition of any one or more ofaspects 1-3, wherein the ratio of the ionic suspension agent to thenon-ionic suspension agent is from 1:8 to 4:1 (aspect 4).

In aspects, the invention provides the composition of any one or more ofaspects 1-4, wherein the chelating agent is disodium edetate in aconcentration of about 0.1 to 0.5 mg/mL (aspect 5).

In aspects, the invention provides the composition of any one or more ofaspects 1-5, wherein the ionic suspension agent comprises an effectiveamount of a hyaluronic acid, carboxymethylcellulose, acacia gum, or amixture of any or all thereof (aspect 6).

In aspects, the invention provides the composition of aspect 6, whereinthe ionic suspension agent is at least mostly composed of hyaluronicacid (aspect 7).

In aspects, the invention provides the composition of aspect 7, whereincomposition comprises hyaluronic acid in a concentration of about 2.0 toabout 20.0 mg/mL (aspect 8).

In aspects, the invention provides the composition of one or both ofaspect 7 or aspect 8, wherein most of the hyaluronic acid in thecomposition hyaluronic acid has a molecular weight is from about 360 toabout 1200 kDa (aspect 9).

In aspects, the invention provides the composition of any one or more ofaspects 7-9, wherein the average molecular weight of most of thehyaluronic acid in the composition is from about 360 to about 1200 kDa(aspect 10).

In aspects, the invention provides the composition of any one or more ofaspects 7-10, wherein the composition comprises chondroitin sulfate in aconcentration of about 5.0 to about 50.0 mg/mL (aspect 11).

In aspects, the invention provides the composition of any one or more ofaspects 1-11, wherein the composition has a pH of from about 6.5 toabout 8.5 (aspect 12).

In aspects, the invention provides the composition of any one or more ofaspects 1-12, wherein the concentration of moxifloxacin is about 0.1% byweight (aspect 13).

In aspects, the invention provides the composition of any one or more ofaspects 1-13, wherein the concentration of loteprednol is about 1.5% byweight (aspect 14).

In aspects, the invention provides the composition of any one or more ofaspects 1-14, wherein the osmolality of the composition is from 200mOsm/kg to 350 mOsm/kg (aspect 15).

In aspects, the invention provides the composition of any one or more ofaspects 1-15, wherein the non-ionic suspension agent is a polysorbate(aspect 16).

In aspects, the invention provides the composition of aspect 16, whereinthe non-ionic suspension agent is polysorbate 80 (aspect 17).

In aspects, the invention provides the composition of aspect 17, whereinthe polysorbate 80 is present in from 5 mg/mL to about 15 mg/mL (aspect18).

In aspects, the invention provides the composition of any one or more ofaspects 1-18, wherein the composition is devoid of a non-ionicpolyoxyethylene-polyoxypropylene block copolymer having the followingchemical structure—HO—(CH2-CH2-O)x-(C3H6-O)y (CH2-CH2-O)x-H, wherein xis an integer having the value of at least 8 and y is an integer havingthe value of at least 38 (aspect 19).

In aspects, the invention provides the composition of any one or more ofaspects 11-19, wherein at least 2 of the ingredients of the compositionare naturally occurring compounds found in the eye (aspect 20).

In aspects, the invention provides the composition of aspect 20, whereinthe at least 2 ingredients are naturally occurring compounds found inthe vitreous humor of the eye (aspect 21).

In aspects, the invention provides the composition of any one or more ofaspects 1-21, wherein at least one ionic suspension agent is an approvedFDA product for intracameral injection (aspect 22).

In aspects, the invention provides the composition of any one or more ofaspects 1-22, wherein at least one ionic suspension agent is a naturalor semi-natural suspension agent having a greater hygroscopicity thanthat of hydroxypropylmethylcellulose (HPMC) (aspect 23).

In aspects, the invention provides the composition of any one or more ofaspects 1-23, wherein at least one ionic suspension agent has a rate ofwater absorption greater than that of xanthan gum (aspect 24).

In aspects, the invention provides the composition of any one or more ofaspects 1-24, wherein at least one ionic suspension agent is a naturalor semi-natural suspension agent having a greater hygroscopicity thanthat of a non-ionic polyoxyethylene-polyoxypropylene block copolymerhaving the following chemicalstructure—HO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein x is aninteger having the value of at least 8 and y is an integer having thevalue of at least 38 (aspect 25).

In aspects, the invention provides the composition of any one or more ofaspects 1-25, wherein the composition is formulated for injection(aspect 26).

In aspects, the invention provides the composition of aspect 26, whereinthe composition is provided in a form ready for injection (aspect 27).

In aspects, the invention provides the composition of aspect 27, whereinthe composition is provided ready for injection in a pre-filled syringe(aspect 28).

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) an effective amount of at least one ionic suspensionagent; (b) an effective amount of at least one non-ionic surfactant; (c)at least two pharmaceutical ingredients comprising (1) moxifloxacin in arange of about 0.01% to about 0.5% by weight, and (2) loteprednol in arange of about 0.1% to about 5% by weight, or a pharmaceuticallyacceptable salts thereof; and (d) a pharmaceutically acceptablechelating agent that results in a significantly similar or improvedstability of the active ingredients as compared to disodium edetate in aconcentration of about 0.1 to 0.5 mg/mL (aspect 29).

In aspects, the invention provides the composition of aspect 29, whereinthe composition comprises only a single ionic suspension agent (aspect30).

In aspects, the invention provides the composition of one or both ofaspect 29 or aspect 30, wherein at least one non-ionic surfactant isalso a non-ionic suspension agent (aspect 31).

In aspects, the invention provides the composition of any one or more ofaspects 29-31, wherein the non-ionic surfactant comprises an effectiveamount of a polysorbate, a polyoxyl-ethylated castor oil, or acombination thereof (aspect 32).

In aspects, the invention provides the composition of any one or more ofaspects 29-32, wherein the ratio of moxifloxacin to the suspension agentcomponent is from 1:10 to 1:32 (aspect 33).

In aspects, the invention provides the composition of any one or more ofaspects 29-33, wherein the ratio of the ionic suspension agent to thenon-ionic suspension agent is from 1:8 to 4:1 (aspect 34).

In aspects, the invention provides the composition of any one or more ofaspects 29-34, wherein the chelating agent is disodium edetate in aconcentration of about 0.1 to 0.5 mg/mL (aspect 35).

In aspects, the invention provides the composition of any one or more ofaspects 29-35, wherein the ionic suspension agent comprises an effectiveamount of a hyaluronic acid, carboxymethylcellulose, acacia gum, or amixture of any or all thereof (aspect 36).

In aspects, the invention provides the composition of aspect 36, whereinthe ionic suspension agent is primarily composed of hyaluronic acid(aspect 37).

In aspects, the invention provides the composition of aspect 37, whereincomposition comprises hyaluronic acid in a concentration of about 2.0 toabout 20.0 mg/mL (aspect 38).

In aspects, the invention provides the composition of one or both ofaspect 37 or aspect 38, wherein most of the hyaluronic acid in thecomposition hyaluronic acid has a molecular weight is from about 360 toabout 1200 kDa (aspect 39).

In aspects, the invention provides the composition of any one or more ofaspects 37-39, wherein the average molecular weight of most of thehyaluronic acid in the composition is from about 360 to about 1200 kDa(aspect 40).

In aspects, the invention provides the composition of any one or more ofaspects 37-40, wherein the composition comprises chondroitin sulfate ina concentration of about 5.0 to about 50.0 mg/mL (aspect 41).

In aspects, the invention provides the composition of any one or more ofaspects 29-41, wherein the composition has a pH of from about 6.5 toabout 8.5 (aspect 42).

In aspects, the invention provides the composition of any one or more ofaspects 29-42, wherein the concentration of moxifloxacin is about 0.1%by weight (aspect 43).

In aspects, the invention provides the composition of any one or more ofaspects 29-43, wherein the concentration of loteprednol is about 1.5% byweight (aspect 44).

In aspects, the invention provides the composition of any one or more ofaspects 29-44, wherein the osmolality of the composition is from 200mOsm/kg to 350 mOsm/kg (aspect 45).

In aspects, the invention provides the composition of aspect 32, whereinthe non-ionic surfactant comprises an effective amount of polysorbate 80(aspect 46).

In aspects, the invention provides the composition of aspect 32, whereinpolysorbate 80 is present in the composition in a concentration of from5 mg/mL to about 15 mg/mL (aspect 47).

In aspects, the invention provides the composition of aspect 32, whereinthe non-ionic surfactant comprises an effective amount of apolyoxyl-ethylated castor oil (aspect 48).

In aspects, the invention provides the composition of aspect 48, whereinthe polyoxyl-ethylated castor oil is present in an amount of from about0.1% to about 1% (aspect 49).

In aspects, the invention provides the composition of one or both ofaspect 48 or aspect 49, wherein the composition comprises an effectiveamount of Cremophor EL (aspect 50).

In aspects, the invention provides the composition of any one or more ofaspects 48-50, wherein the composition comprises an effective amount ofCremophor RH-40 (aspect 51).

In aspects, the invention provides the composition of any one or more ofaspects 29-51, wherein the composition is devoid of a non-ionicpolyoxyethylene-polyoxypropylene block copolymer having the followingchemical structure—HO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein xis an integer having the value of at least 8 and y is an integer havingthe value of at least 38 (aspect 52).

In aspects, the invention provides the composition of any one or more ofaspects 41-52, wherein at least 2 of the ingredients of the compositionare naturally occurring compounds found in the eye (aspect 53).

In aspects, the invention provides the composition of aspect 53, whereinthe at least 2 ingredients are naturally occurring compounds found inthe vitreous humor of the eye (aspect 54).

In aspects, the invention provides the composition of any one or more ofaspects 29-54, wherein at least one ionic suspension agent is anapproved FDA product for intracameral injection (aspect 55).

In aspects, the invention provides the composition of any one or more ofaspects 29-55, wherein at least one ionic suspension agent is a naturalor semi-natural suspension agent having a greater hygroscopicity thanthat of hydroxypropylmethylcellulose (HPMC) (aspect 56).

In aspects, the invention provides the composition of any one or more ofaspects 29-56, wherein at least one ionic suspension agent has a rate ofwater absorption greater than that of xanthan gum (aspect 57).

In aspects, the invention provides the composition of any one or more ofaspects 29-57, wherein at least one ionic suspension agent is a naturalor semi-natural suspension agent having a greater hygroscopicity thanthat of a non-ionic polyoxyethylene-polyoxypropylene block copolymerhaving the following chemicalstructure—HO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein x is aninteger having the value of at least 8 and y is an integer having thevalue of at least 38 (aspect 58).

In aspects, the invention provides the composition of any one or more ofaspects 29-58, wherein the composition is formulated for injection(aspect 59).

In aspects, the invention provides the composition of aspect 59, whereinthe composition is provided in a form ready for injection (aspect 60).

In aspects, the invention provides the composition of aspect 60, whereinthe composition is provided ready for injection in a pre-filled syringe(aspect 61).

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) at least 1.5 wt. % of a suspension agent componentcomprising an effective amount of a natural or semi-synthetic suspensionagent other than xanthan gum; (b) at least two pharmaceuticalingredients comprising (1) moxifloxacin in a range of about 0.01% toabout 0.5% by weight, and (2) loteprednol in a range of about 0.1% toabout 5% by weight, or pharmaceutically acceptable salts thereof; and(c) a pharmaceutically acceptable chelating agent that results in asignificantly similar or improved stability of the active ingredients ascompared to disodium edetate in a concentration of about 0.1 to 0.5mg/mL, (d) wherein (a) the composition has a viscosity of about3.5-about 25 mPas and (b) the composition exhibits significantly lessflocculation, coagulation, clumping, or combination of any or allthereof as opposed to a corresponding formulation comprising xanthan gumin place of the suspension agent (aspect 62).

In aspects, the invention provides the composition of aspect 62, whereinthe composition comprises only a single natural or semi-syntheticsuspension agent (aspect 63).

In aspects, the invention provides the composition of one or both ofaspect 62 or aspect 63, wherein the composition further comprises aneffective amount of a non-ionic surfactant (aspect 64).

In aspects, the invention provides the composition of aspect 64, whereinthe non-ionic surfactant is also a suspension agent (aspect 65).

In aspects, the invention provides the composition of one or both ofaspect 64 or aspect 65, wherein the non-ionic surfactant comprises aneffective amount of a polysorbate, a polyoxyl-ethylated castor oil, or acombination thereof (aspect 66).

In aspects, the invention provides the composition of any one or more ofaspects 62-66, wherein the ratio of moxifloxacin to the suspension agentcomponent is from 1:10 to 1:32 (aspect 67).

In aspects, the invention provides the composition of any one or more ofaspects 62-67, wherein the ratio of the ionic suspension agent to thenon-ionic suspension agent is from 1:8 to 4:1 (aspect 68).

In aspects, the invention provides the composition of any one or more ofaspects 62-68, wherein the chelating agent is disodium edetate in aconcentration of about 0.1 to 0.5 mg/mL (aspect 69).

In aspects, the invention provides the composition of any one or more ofaspects 62-69, wherein the suspension agent has an average molecularweight of less than 1200 kDa (aspect 70).

In aspects, the invention provides the composition of aspect 70, whereinthe suspension agent has an average molecular weight of less than 1000kDa (aspect 71).

In aspects, the invention provides the composition of any one or more ofaspects 62-71, wherein the suspension agent comprises an effectiveamount of a hyaluronic acid, carboxymethylcellulose, acacia gum, or amixture of any or all thereof (aspect 72).

In aspects, the invention provides the composition of any one or more ofaspects 62-72, wherein the suspension agent comprises an effectiveamount of hyaluronic acid (aspect 73).

In aspects, the invention provides the composition of any one or more ofaspects 62-72, wherein composition comprises hyaluronic acid in aconcentration of about 2.0 to about 20.0 mg/mL (aspect 74).

In aspects, the invention provides the composition of one or both ofaspect 73 or aspect 74, wherein most of the hyaluronic acid in thecomposition hyaluronic acid has a molecular weight is from about 360 toabout 1200 kDa (aspect 75).

In aspects, the invention provides the composition of any one or more ofaspects 73-75, wherein the average molecular weight of most of thehyaluronic acid in the composition is from about 360 to about 1200 kDa(aspect 76).

In aspects, the invention provides the composition of any one or more ofaspects 73-76, wherein the composition comprises chondroitin sulfate ina concentration of about 5.0 to about 50.0 mg/mL (aspect 77).

In aspects, the invention provides the composition of any one or more ofaspects 62-77, wherein the composition has a pH of from about 6.5 toabout 8.5 (aspect 78).

In aspects, the invention provides the composition of any one or more ofaspects 62-78, wherein the concentration of moxifloxacin is about 0.1%by weight (aspect 79).

In aspects, the invention provides the composition of any one or more ofaspects 62-79, wherein the concentration of loteprednol is about 1.5% byweight (aspect 80).

In aspects, the invention provides the composition of any one or more ofaspects 62-80, wherein the osmolality of the composition is from 200mOsm/kg to 350 mOsm/kg (aspect 81).

In aspects, the invention provides the composition of aspect 65, whereinthe non-ionic suspension agent comprises an effective amount of apolysorbate (aspect 82).

In aspects, the invention provides the composition of aspect 82, whereinthe non-ionic suspension agent is polysorbate 80 (aspect 83).

In aspects, the invention provides the composition of aspect 83, whereinthe polysorbate 80 is present in from 5 mg/mL to about 15 mg/mL (aspect84).

In aspects, the invention provides the composition of any one or more ofaspects 62-84, wherein the composition is devoid of a non-ionicpolyoxyethylene-polyoxypropylene block copolymer having the followingchemical structure—HO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein xis an integer having the value of at least 8 and y is an integer havingthe value of at least 38 (aspect 85).

In aspects, the invention provides the composition of any one or more ofaspects 62-85, wherein the composition is free of hydroxypropylmethylcellulose (aspect 86).

In aspects, the invention provides the composition of any one or more ofaspects 78-86, wherein at least 2 of the ingredients of the compositionare naturally occurring compounds found in the eye (aspect 87).

In aspects, the invention provides the composition of aspect 87, whereinthe at least 2 ingredients are naturally occurring compounds found inthe vitreous humor of the eye (aspect 88).

In aspects, the invention provides the composition of any one or more ofaspects 62-88, wherein at least one ionic suspension agent is anapproved FDA product for intracameral injection (aspect 89).

In aspects, the invention provides the composition of any one or more ofaspects 62-89, wherein at least one ionic suspension agent is a naturalor semi-natural suspension agent having a greater hygroscopicity thanthat of hydroxypropylmethylcellulose (HPMC) (aspect 90).

In aspects, the invention provides the composition of any one or more ofaspects 62-90, wherein at least one ionic suspension agent has a rate ofwater absorption greater than that of xanthan gum (aspect 91).

In aspects, the invention provides the composition of any one or more ofaspects 62-91, wherein at least one ionic suspension agent is a naturalor semi-natural suspension agent having a greater hygroscopicity thanthat of a non-ionic polyoxyethylene-polyoxypropylene block copolymerhaving the following chemicalstructure—HO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein x is aninteger having the value of at least 8 and y is an integer having thevalue of at least 38 (aspect 92).

In aspects, the invention provides the composition of any one or more ofaspects 62-92, wherein the composition is formulated for injection(aspect 93).

In aspects, the invention provides the composition of aspect 93, whereinthe composition is provided in a form ready for injection (aspect 94).

In aspects, the invention provides the composition of aspect 94, whereinthe composition is provided ready for injection in a pre-filled syringe(aspect 95).

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) an effective amount of least one natural orsemi-synthetic suspension agent composed of a compound having an averagemolecular weight of between 10,000 and 1,000,000 Daltons; (b) at leasttwo pharmaceutical ingredients comprising (1) moxifloxacin in a range ofabout 0.01% to about 0.5% by weight, and (2) loteprednol in a range ofabout 0.1% to about 5% by weight, or a pharmaceutically acceptable saltsthereof; and (c) a pharmaceutically acceptable chelating agent thatresults in a significantly similar or improved stability of the activeingredients as compared to disodium edetate in a concentration of about0.1 to 0.5 mg/mL (aspect 96).

In aspects, the invention provides the composition of aspect 96, whereinthe composition comprises only a single natural or semi-syntheticsuspension agent (aspect 97).

In aspects, the invention provides the composition of one or both ofaspect 96 or aspect 97, wherein the composition further comprises aneffective amount of a non-ionic surfactant (aspect 98).

In aspects, the invention provides the composition of aspect 98, whereinthe non-ionic surfactant is also a suspension agent (aspect 99).

In aspects, the invention provides the composition of one or both ofaspect 98 or aspect 99, wherein the non-ionic surfactant comprises aneffective amount of a polysorbate, a polyoxyl-ethylated castor oil, or acombination thereof (aspect 100).

In aspects, the invention provides the composition of any one or more ofaspects 96-100, wherein the ratio of moxifloxacin to the suspensionagent component is from 1:10 to 1:32 (aspect 101).

In aspects, the invention provides the composition of any one or more ofaspects 96-101, wherein the ratio of the ionic suspension agent to thenon-ionic suspension agent is from 1:8 and 4:1 (aspect 102).

In aspects, the invention provides the composition of any one or more ofaspects 96-102, wherein the chelating agent is disodium edetate in aconcentration of about 0.1 to 0.5 mg/mL (aspect 103).

In aspects, the invention provides the composition of any one or more ofaspects 96-103, wherein the suspension agent comprises an effectiveamount of a hyaluronic acid, acacia gum, or a mixture of any or allthereof (aspect 104).

In aspects, the invention provides the composition of any one or more ofaspects 96-104, wherein the suspension agent comprises an effectiveamount of hyaluronic acid (aspect 105).

In aspects, the invention provides the composition of any one or more ofaspects 96-104, wherein composition comprises hyaluronic acid in aconcentration of about 2.0 to about 20.0 mg/mL (aspect 106).

In aspects, the invention provides the composition of one or both ofaspect 105 or aspect 106, wherein most of the hyaluronic acid in thecomposition hyaluronic acid has a molecular weight is from about 360 toabout 1200 kDa (aspect 107).

In aspects, the invention provides the composition of any one or more ofaspects 105-107, wherein the average molecular weight of most of thehyaluronic acid in the composition is from about 360 to about 1200 kDa(aspect 108).

In aspects, the invention provides the composition of any one or more ofaspects 105-107, wherein the composition comprises chondroitin sulfatein a concentration of about 5.0 to about 50.0 mg/mL (aspect 109).

In aspects, the invention provides the composition of any one or more ofaspects 96-109, wherein the composition has a pH of from about 6.5 toabout 8.5 (aspect 110).

In aspects, the invention provides the composition of any one or more ofaspects 96-110, wherein the concentration of moxifloxacin is about 0.5%by weight (aspect 111).

In aspects, the invention provides the composition of any one or more ofaspects 96-111, wherein the concentration of loteprednol is about 1.5%by weight (aspect 112).

In aspects, the invention provides the composition of any one or more ofaspects 96-112, wherein the osmolality of the composition is from 200mOsm/kg to 350 mOsm/kg (aspect 113).

In aspects, the invention provides the composition of aspect 100,wherein the non-ionic suspension agent comprises an effective amount ofa polysorbate (aspect 114).

In aspects, the invention provides the composition of aspect 114,wherein the non-ionic suspension agent is polysorbate 80 (aspect 115).

In aspects, the invention provides the composition of aspect 115,wherein the polysorbate 80 is present in from 5 mg/mL to about 15 mg/mL(aspect 116).

In aspects, the invention provides the composition of one or both ofaspects 96-116, wherein the composition is devoid of a non-ionicpolyoxyethylene-polyoxypropylene block copolymer having the followingchemical structure—HO—(CH2-CH2-O)x-(C3H6-O)y (CH2-CH2-O)x-H, wherein xis an integer having the value of at least 8 and y is an integer havingthe value of at least 38 (aspect 117).

In aspects, the invention provides the composition of one or both ofaspects 96-117, wherein the composition is free of hydroxypropylmethylcellulose (aspect 118).

In aspects, the invention provides the composition of one or both ofaspects 109-118, wherein at least 2 of the ingredients of thecomposition are naturally occurring compounds found in the eye (aspect119).

In aspects, the invention provides the composition of aspect 119,wherein the at least 2 ingredients are naturally occurring compoundsfound in the vitreous humor of the eye (aspect 120).

In aspects, the invention provides the composition of one or both ofaspects 96-120, wherein at least one ionic suspension agent is anapproved FDA product for intracameral injection (aspect 121).

In aspects, the invention provides the composition of one or both ofaspects 96-121, wherein at least one ionic suspension agent is a naturalor semi-natural suspension agent having a greater hygroscopicity thanthat of hydroxypropylmethylcellulose (HPMC) (aspect 122).

In aspects, the invention provides the composition of one or both ofaspects 96-122, wherein at least one ionic suspension agent has a rateof water absorption greater than that of xanthan gum (aspect 123).

In aspects, the invention provides the composition of one or both ofaspects 96-123, wherein at least one ionic suspension agent is a naturalor semi-natural suspension agent having a greater hygroscopicity thanthat of a non-ionic polyoxyethylene-polyoxypropylene block copolymerhaving the following chemicalstructure—HO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein x is aninteger having the value of at least 8 and y is an integer having thevalue of at least 38 (aspect 124).

In aspects, the invention provides the composition of one or both ofaspects 96-124, wherein the composition is formulated for injection(aspect 125).

In aspects, the invention provides the composition of aspect 125,wherein the composition is provided in a form ready for injection(aspect 126).

In aspects, the invention provides the composition of aspect 126,wherein the composition is provided ready for injection in a pre-filledsyringe (aspect 127).

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) an effective amount of a suspension agent comprisingeffective amounts of two nonionic suspension agents, one of whichnonionic suspension agents having surface active activity; (b) at leasttwo pharmaceutical ingredients comprising (1) moxifloxacin in a range ofabout 0.01% to about 0.5% by weight, and (2) loteprednol in a range ofabout 0.1% to about 5% by weight, or pharmaceutically acceptable saltsthereof; and (c) a pharmaceutically acceptable chelating agent thatresults in a significantly similar or improved stability of the activeingredients as compared to disodium edetate in a concentration of about0.1 to 0.5 mg/mL (aspect 128).

In aspects, the invention provides the composition of aspect 128,wherein the composition comprises only two suspension agents (aspect129).

In aspects, the invention provides the composition of one or both ofaspect 128 or aspect 129, wherein non-ionic suspension agent that is anon-ionic surfactant comprises an effective amount of a polysorbate, apolyoxyl-ethylated castor oil, or a combination thereof (aspect 130).

In aspects, the invention provides the composition of any one or more ofaspects 128-130, wherein the ratio of moxifloxacin to the suspensionagent component is from 1:10 to 1:32 (aspect 131).

In aspects, the invention provides the composition of any one or more ofaspects 128-131, wherein the ratio of the ionic suspension agent to thenonionic suspension agent is from 1:8 and 4:1 (aspect 132).

In aspects, the invention provides the composition of any one or more ofaspects 128-132, wherein the chelating agent is disodium edetate in aconcentration of about 0.1 to 0.5 mg/mL (aspect 133).

In aspects, the invention provides the composition of any one or more ofaspects 128-133, wherein the suspension agent that is not a non-ionicsurfactant comprises an effective amount of a hyaluronic acid, acaciagum, or a mixture of any or all thereof (aspect 134).

In aspects, the invention provides the composition of aspect 133,wherein the suspension agent comprises an effective amount of hyaluronicacid (aspect 135).

In aspects, the invention provides the composition of aspect 133,wherein composition comprises hyaluronic acid in a concentration ofabout 2.0 to about 20.0 mg/mL (aspect 136).

In aspects, the invention provides the composition of one or both ofaspect 135 or aspect 136, wherein most of the hyaluronic acid in thecomposition hyaluronic acid has a molecular weight is from about 360 toabout 1200 kDa (aspect 137).

In aspects, the invention provides the composition of any one or more ofaspects 135-137, wherein the average molecular weight of most of thehyaluronic acid in the composition is from about 360 to about 1200 kDa(aspect 138).

In aspects, the invention provides the composition of any one or more ofaspects 135-138, wherein the composition comprises chondroitin sulfatein a concentration of about 5.0 to about 50.0 mg/mL (aspect 139).

In aspects, the invention provides the composition of any one or more ofaspects 128-139, wherein the composition has a pH of from about 6.5 toabout 8.5 (aspect 140).

In aspects, the invention provides the composition of any one or more ofaspects 128-140, wherein the concentration of moxifloxacin is about 0.1%by weight (aspect 141).

In aspects, the invention provides the composition of any one or more ofaspects 128-141, wherein the concentration of loteprednol is about 1.5%by weight (aspect 142).

In aspects, the invention provides the composition of any one or more ofaspects 128-142, wherein the osmolality of the composition is from 200mOsm/kg to 350 mOsm/kg (aspect 143).

In aspects, the invention provides the composition of aspect 130,wherein the non-ionic suspension agent that is a non-ionic surfactantcomprises an effective amount of a polysorbate (aspect 144).

In aspects, the invention provides the composition of aspect 144,wherein the non-ionic suspension agent that is a non-ionic surfactant ispolysorbate 80 (aspect 145).

In aspects, the invention provides the composition of aspect 145,wherein the polysorbate 80 is present in from 5 mg/mL to about 15 mg/mL(aspect 146).

In aspects, the invention provides the composition of any one or more ofaspects 128-146, wherein the composition is devoid of a non-ionicpolyoxyethylene-polyoxypropylene block copolymer having the followingchemical structure—HO—(CH2-CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein xis an integer having the value of at least 8 and y is an integer havingthe value of at least 38 (aspect 147).

In aspects, the invention provides the composition of any one or more ofaspects 128-147, wherein the composition is free of hydroxypropylmethylcellulose (aspect 148).

In aspects, the invention provides the composition of any one or more ofaspects 139-148, wherein at least 2 of the ingredients of thecomposition are naturally occurring compounds found in the eye (aspect149).

In aspects, the invention provides the composition of aspect 149,wherein the at least 2 ingredients are naturally occurring compoundsfound in the vitreous humor of the eye (aspect 150).

In aspects, the invention provides the composition of any one or more ofaspects 128-150, wherein at least one ionic suspension agent is anapproved FDA product for intracameral injection (aspect 151).

In aspects, the invention provides the composition of any one or more ofaspects 128-151, wherein at least one ionic suspension agent is anatural or semi-natural suspension agent having a greater hygroscopicitythan that of hydroxypropylmethylcellulose (HPMC) (aspect 152).

In aspects, the invention provides the composition of any one or more ofaspects 128-152, wherein at least one ionic suspension agent has a rateof water absorption greater than that of xanthan gum (aspect 153).

In aspects, the invention provides the composition of any one or more ofaspects 128-153, wherein at least one ionic suspension agent is anatural or semi-natural suspension agent having a greater hygroscopicitythan that of a non-ionic polyoxyethylene-polyoxypropylene blockcopolymer having the following chemical structure—HO—(CH2CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein x is an integer having thevalue of at least 8 and y is an integer having the value of at least 38(aspect 154).

In aspects, the invention provides the composition of any one or more ofaspects 128-154, wherein the composition is formulated for injection(aspect 155).

In aspects, the invention provides the composition of aspect 155,wherein the composition is provided in a form ready for injection(aspect 156).

In aspects, the invention provides the composition of aspect 156,wherein the composition is provided ready for injection in a pre-filledsyringe (aspect 157).

In aspects, the invention provides an ophthalmologically suitablepharmaceutical composition in the form of a solution or suspensioncomprising: (a) an effective amount of a suspension agent; (b) aneffective amount of a polyoxyl-ethylated castor oil; (c) at least twopharmaceutical ingredients comprising (1) moxifloxacin in a range ofabout 0.01% to about 0.5% by weight, and (2) loteprednol in a range ofabout 0.1% to about 5% by weight, or pharmaceutically acceptable saltsthereof; and (d) a pharmaceutically acceptable chelating agent thatresults in a significantly similar or improved stability of the activeingredients as compared to disodium edetate in a concentration of about0.1 to 0.5 mg/mL (aspect 158).

In aspects, the invention provides the composition of aspect 158,wherein the composition comprises from about 0.1-about 1% ofpolyoxyl-ethylated castor oil (aspect 159).

In aspects, the invention provides the composition of one or both ofaspect 158 or aspect 159, wherein the composition comprises an effectiveamount of Cremophor EL (aspect 160).

In aspects, the invention provides the composition of one or both ofaspect 158 or aspect 159, wherein the composition comprises an effectiveamount of Cremophor RH-40 (aspect 161).

In aspects, the invention provides the composition of any one or more ofaspects 158-161, wherein the composition comprises only a singlesuspension agent (aspect 162).

In aspects, the invention provides the composition of any one or more ofaspects 158-162, wherein the ratio of moxifloxacin to the suspensionagent component is from 1:10 to 1:32 (aspect 163).

In aspects, the invention provides the composition of any one or more ofaspects 158-163, wherein the ratio of the ionic suspension agent to thenon-ionic suspension agent is from 1:8 to 4:1 (aspect 164).

In aspects, the invention provides the composition of any one or more ofaspects 158-164, wherein the chelating agent is disodium edetate in aconcentration of about 0.1 to 0.5 mg/mL (aspect 165).

In aspects, the invention provides the composition of any one or more ofaspects 158-165, wherein the suspension agent is an ionic suspensionagent (aspect 166).

The composition of aspect 166, wherein the ionic suspension agentcomprises an effective amount of a hyaluronic acid,carboxymethylcellulose, acacia gum, or a mixture of any or all thereof(aspect 167).

In aspects, the invention provides the composition of aspect 167,wherein the ionic suspension agent comprises an effective amount ofhyaluronic acid (aspect 168).

In aspects, the invention provides the composition of aspect 168,wherein composition comprises hyaluronic acid in a concentration ofabout 2.0 to about 20.0 mg/mL (aspect 169).

In aspects, the invention provides the composition of one or both ofaspect 168 or aspect 169, wherein most of the hyaluronic acid in thecomposition hyaluronic acid has a molecular weight is from about 360 toabout 1200 kDa (aspect 170).

The composition of any one or more of aspects 168-170, wherein theaverage molecular weight of most of the hyaluronic acid in thecomposition is from about 360 to about 1200 kDa (aspect 171).

In aspects, the invention provides the composition of any one or more ofaspects 168-171, wherein the composition comprises chondroitin sulfatein a concentration of about 5.0 to about 50.0 mg/mL (aspect 172).

In aspects, the invention provides the composition of aspect 167,wherein the composition comprises an effective amount ofcarboxymethylcellulose (aspect 173).

In aspects, the invention provides the composition of any one or more ofaspects 158-165, wherein the suspension agent is a non-ionic suspensionagent (aspect 174).

In aspects, the invention provides the composition of aspect 174,wherein the non-ionic suspension agent comprises an effective amount ofmethylcellulose, hydroxyethylcellulose, gelatin, polyvinylpyrrolidone,polyethylene glycol, or a mixture of any or all thereof (aspect 175).

In aspects, the invention provides the composition of any one or more ofaspects 158-172, wherein the composition has a pH of from about 6.5 toabout 8.5 (aspect 176).

In aspects, the invention provides the composition of any one or more ofaspects 158-176, wherein the concentration of moxifloxacin is about 0.1%by weight (aspect 177).

In aspects, the invention provides the composition of any one or more ofaspects 158-177, wherein the concentration of loteprednol is about 1.5%by weight (aspect 178).

In aspects, the invention provides the composition of any one or more ofaspects 158-178, wherein the osmolality of the composition is from 200mOsm/kg to 350 mOsm/kg (aspect 179).

In aspects, the invention provides the composition of any one or more ofaspects 172-179, wherein at least 2 of the ingredients of thecomposition are naturally occurring compounds found in the eye (aspect180).

In aspects, the invention provides the composition of aspect 180,wherein the at least 2 ingredients are naturally occurring compoundsfound in the vitreous humor of the eye (aspect 181).

In aspects, the invention provides the composition of any one or more ofaspects 158-181, wherein at least one ionic suspension agent is anapproved FDA product for intracameral injection (aspect 182).

In aspects, the invention provides the composition of any one or more ofaspects 158-182, wherein at least one ionic suspension agent is anatural or semi-natural suspension agent having a greater hygroscopicitythan that of hydroxypropylmethylcellulose (HPMC) (aspect 183).

In aspects, the invention provides the composition of any one or more ofaspects 158-183, wherein at least one ionic suspension agent has a rateof water absorption greater than that of xanthan gum (aspect 184).

In aspects, the invention provides the composition of any one or more ofaspects 158-184, wherein at least one ionic suspension agent is anatural or semi-natural suspension agent having a greater hygroscopicitythan that of a non-ionic polyoxyethylene-polyoxypropylene blockcopolymer having the following chemical structure—HO—(CH2CH2-O)x-(C3H6-O)y-(CH2-CH2-O)x-H, wherein x is an integer having thevalue of at least 8 and y is an integer having the value of at least 38(aspect 185).

In aspects, the invention provides the composition of any one or more ofaspects 158-185, wherein the composition is formulated for injection(aspect 186).

In aspects, the invention provides the composition of aspect 186,wherein the composition is provided in a form ready for injection(aspect 187).

In aspects, the invention provides the composition of aspect 187,wherein the composition is provided ready for injection in a pre-filledsyringe (aspect 188).

In aspects, the invention provides a kit comprising a pharmaceuticallyacceptable composition of any one or more of aspects 1-188 packaged inone or more single use containers, wherein the kit further comprises oneor more delivery devices for administering the composition to arecipient (aspect 189).

In aspects, the invention provides the kit of aspect 189, wherein thedelivery device is a syringe system (aspect 190).

In aspects, the invention provides the kit of aspect 190, wherein thedelivery device is a syringe system wherein any single use containercomprising a pharmaceutically acceptable composition present in the kitis accessible to a delivery device/system of the kit, such as, e.g.,containing a stopper which effectively seals the single use containerbut which is penetrable by the delivery device/system such that thedelivery device can extract the composition from the single usecontainer (aspect 191).

In aspects, the invention provides the kit of aspect 190 or aspect 191,wherein the delivery system is a syringe system and wherein thecomposition(s) are individual packaged in pre-filled syringes (aspect192).

In aspects, the invention provides the kit of aspect 192, wherein 1 ormore individual doses of between about 0.5 mL-about 5 mL of compositionare provided (aspect 193).

In aspects, the invention provides the kit of aspects 189-193, whereinthe delivery system is a dropper bottle for providing the composition ina drop-by-drop manner (aspect 194).

In aspects, the invention provides the kit of [0689], wherein the kitcomprises one or more dropper bottles each comprising between about 1 mLand about 10 mL of a carrier composition (aspect 195).

In aspects, the invention provides a method of using any one or morepharmaceutically acceptable and ophthalmologically suitable compositionsdescribed herein to treat or prevent inflammation associated withphysical trauma to ophthalmic tissue(s), inflammation associated withmicrobial (e.g., bacterial) infection(s), inflammation resulting fromsurgical procedure(s), or any combination thereof (aspect 196).

In aspects, the invention provides a method of using any one or morepharmaceutically acceptable and ophthalmologically suitable compositionsdescribed herein to treat or prevent an ocular microbial infection(aspect 197).

In aspects, the invention provides a method of using any one or morepharmaceutically acceptable and ophthalmologically suitable compositionsdescribed herein to treat or prevent significant inflammation associatedwith physical trauma to ophthalmic tissue(s), significant inflammationassociated with microbial (e.g., bacterial) infection(s), inflammationresulting from surgical procedure(s), to treat or prevent an ocularmicrobial infection, or any combination thereof (aspect 198).

In aspects, the invention provides the method of any one or more ofaspects 196-198, wherein the method comprises providing the any one ormore pharmaceutically acceptable and ophthalmologically suitablecompositions for use in the method as a kit of any one or more ofaspects 189-195 (aspect 199).

In aspects, the invention provides the method of any one or more ofaspects 196-199, wherein the pharmaceutically acceptable andophthalmologically suitable composition is delivered to the eye in acontrolled manner (aspect 200).

In aspects, the invention provides the method of any one or more ofaspects 196-200, wherein the pharmaceutically acceptable andophthalmologically suitable composition is delivered in a drop-by-dropmanner (aspect 201).

In aspects, the invention provides the method of any one or more ofaspects 196-201, wherein the pharmaceutically acceptable andophthalmologically suitable composition is delivered to the eye byinjection, e.g., by intracameral injection (aspect 202).

In aspects, the invention provides a method of treating or preventing adisease or condition benefiting from a combination therapy of anquinolone antibiotic antimicrobial component and a steroid or steroidand non-steroid anti-inflammatory component, the method comprisingadministering an effective amount of a pharmaceutically acceptable andophthalmologically suitable composition, comprising pharmaceuticallyacceptable amounts of any one or more compositions of aspects 1-202(aspect 203).

In aspects, the invention provides the method of aspect 203, wherein thedisease or condition is bacterial conjunctivitis (aspect 204).

In aspects, the invention provides the method of aspect 203, wherein thedisease or condition is an ocular infection (aspect 205).

In aspects, the invention provides the method of aspect 203, wherein thedisease or condition is an ocular infection, inflammation, or botharising after an invasive ophthalmic procedure (aspect 206).

In aspects, the invention provides the method of aspect 203, wherein theophthalmologically-related procedure is selected from a group comprisingcataract surgery and intraocular lens replacement (aspect 207).

In aspects, the invention provides the method of aspect 203, wherein thedisease or condition is conjunctivitis, keratitis, blepharitis,dacryocytitis, hordeoleum, and corneal ulcers (aspect 208).

In aspects, the invention provides the method of any one or more ofaspects 203-208 wherein the method comprises providing the any one ormore pharmaceutically acceptable and ophthalmologically suitablecompositions for use in the method as a kit of any one or more ofaspects 189-195 (aspect 209).

In aspects, the invention provides the method of any one or more ofaspects 203-209, wherein the pharmaceutically acceptable andophthalmologically suitable composition is delivered in a drop-by-dropmanner (aspect 210).

In aspects, the invention provides the method of any one or more ofaspects 203-210, wherein the pharmaceutically acceptable andophthalmologically suitable composition is administered prior to anophthalmologically-related procedure (aspect 211).

In aspects, the invention provides the method of any one or more ofaspects 203-211, wherein the pharmaceutically acceptable andophthalmologically suitable composition is administered for a periodfollowing an ophthalmologically-related procedure (aspect 212).

In aspects, the invention provides the method of any one or more ofaspects 203-212, wherein the pharmaceutically acceptable andophthalmologically suitable composition is administered over anadministration period ranging from a one-time administration to anadministration of twice, or three times per day for a period of betweenabout 1-7 days (aspect 213).

In aspects, the invention provides the method of any one or more ofaspects 203-213, wherein treatment with the pharmaceutically acceptableand ophthalmologically suitable composition provides detectably orsignificantly fewer side effects selected from a group accommodationdisturbance, anterior uveitis, blepharitis, conjunctival hyperemia,conjunctivitis, corneal perforation or ulcer, decreased visual acuity,eye infection, glaucoma, increased intraocular pressure, keratitis,mydriasis, optic nerve damage, visual field defect, wound healingimpairment, conjunctival irritation, dysgeusia, eye discharge, eyeirritation, eye pain, eye redness, eyelid edema, headache, increasedlacrimation, papillary conjunctivitis, pyrexia, subconjunctivalhemorrhage, tearing, abnormal sensation in eye(s), anterior chamber eyehemorrhage, burning, corneal erosion, corneal thinning, epithelialkeratopathy, pruritis, iritis, prolonged bleeding, stinging, orhypersensitivity reaction than treatment with any one or more ofImprimusRx Moxifloxacin Intraocular Solution for Injection, ImprimusRxPrednisolone Acetate Moxifloxacin Ophthalmic Suspension, ImprimusRxPrednisolone Acetate Moxifloxacin Nepafenac Ophthalmic Suspension,ImprimusRx Prednisolone-Bromfenac Suspension, ImprimusRxPrednisolone-Bromfenac Ophthalmic Drops, ImprimusRx Prednisolone SodiumPhosphate Bromfenac Ophthalmic Solution, ImprimusRxPrednisolone-Gatifloxacin-Bromfenac Ophthalmic Drops, ImprimusRxPrednisolone Acetate Moxifloxacin Bromfenac Ophthalmic Suspension, andImprimusRx Triamcinolone Acetonide Moxifloxacin HCl IntraocularSuspension for Injection (aspect 214).

EXAMPLES (TRIAMCINOLONE+MOXIFLOXACIN)

The following ophthalmologically suitableantimicrobial-anti-inflammatory combination formulations of Table 2 weregenerated according to the following procedures.

TABLE 2 Exemplary Formulations. QUANTITY/mL (mg) INGREDIENT Form. IForm. II Form. III Form. IV Form. V Triamcinolone 10.0-20.0 10.0-20.010.0-20.0 10.0-20.0  1.0-30.0 acetonide (as base) Moxifloxacin HCl 1.01.0 1.0 1.0 1.0 (as base) Polysorbate-80 10.0 10.0 10.0 10.0 10.0Polyethylene glycol —  10.0-100.0 — — 3350 (PEG 3350) Hyaluronic acid 2.0-20.0 — —  2.0-20.0  2.0-20.0 Sodium — —  2.0-20.0 — — carboxymethylcellulose (CMC) Chondroitin sulfate — — — 5.0-50.0  50-50.0 Sodiumcitrate  1.0-10.0  1.0-10.0  1.0-10.0  1.0-10.0  1.0-10.0 monohydrateDisodium edetate 1.0-5.0 1.0-5.0 1.0-5.0 1.0-5.0 1.0-5.0 dihydrateBenzalkonium — — — — 0.05 chloride Hydrochloric acid/ QS to adjust QS toadjust QS to adjust QS to adjust QS to adjust sodium hydroxide pH to pHto pH to pH to pH to 7.0 ± 0.2 7.0 ± 0.2 7.0 ± 0.2 7.0 ± 0.2 7.0 ± 0.2Water QS to 1.0 QS to 1.0 QS to 1.0 QS to 1.0 QS to 1.0 mL mL mL mL mL(“Form.” = formulation)

Example 1 Moxifloxacin Hydrochloride and Triamcinolone AcetonideOphthalmic Suspension (Single Dose)

The composition having Formulation I was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of triamcinolone acetonide was added to        30% of the total required volume of water forming a        triamcinolone acetonide suspension.    -   2. The triamcinolone acetonide suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 0.5-1.5 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part II:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 50% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. The total quantity of hyaluronic acid was added to the        completely dissolved solution of sodium citrate monohydrate,        polysorbate-80, and disodium edetate dihydrate and stirred for 2        hours at moderate speed (to ensure complete dissolution of the        hyaluronic acid).    -   5. Upon complete dissolution of the hyaluronic acid, the        resulting solution was autoclaved at 121° C. for 20 minutes.    -   6. The solution was allowed to cool after autoclaving.    -   7. Once the solution was cooled to room temperature, the total        quantity of moxifloxacin was added and allowed to completely        dissolve.    -   8. The resulting solution was QS to 65% of the final volume.    -   9. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 2 Moxifloxacin Hydrochloride and Triamcinolone AcetonideOphthalmic Suspension (Single Dose)

The composition having Formulation II was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of triamcinolone acetonide was added to        30% of the total required volume of water forming a        triamcinolone acetonide suspension.    -   2. The triamcinolone acetonide suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 0.5-1.5 μm.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part II:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate        in the sodium citrate monohydrate and polysorbate-80 solution,        the complete quantity of moxifloxacin hydrochloride was added        and stirred until completely dissolved.    -   5. Upon complete dissolution of moxifloxacin hydrochloride, the        total quantity of PEG 3350 was added to the completely dissolved        solution of sodium citrate monohydrate, polysorbate-80, disodium        edetate dihydrate and moxifloxacin hydrochloride and stirred for        2 hours at moderate speed (to ensure complete dissolution of the        PEG 3350).    -   6. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   7. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 3 Moxifloxacin Hydrochloride and Triamcinolone AcetonideOphthalmic Suspension (Single Dose)

The composition having Formulation III was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of triamcinolone acetonide was added to        30% of the total required volume of water forming a        triamcinolone acetonide suspension.    -   2. The triamcinolone acetonide suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 0.5-1.5 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate        in the sodium citrate monohydrate and polysorbate-80 solution,        the complete quantity of moxifloxacin hydrochloride was added        and stirred until completely dissolved.    -   5. Upon complete dissolution of moxifloxacin hydrochloride, the        total quantity of CMC was added to the completely dissolved        solution of sodium citrate monohydrate, polysorbate-80, disodium        edetate dihydrate and moxifloxacin hydrochloride and stirred for        2 hours at moderate speed (to ensure complete dissolution of the        CMC).    -   6. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   7. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI.

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 4 Moxifloxacin Hydrochloride and Triamcinolone AcetonideOphthalmic Suspension (Single Dose)

The composition having Formulation IV was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of triamcinolone acetonide was added to        30% of the total required volume of water forming a        triamcinolone acetonide suspension.    -   2. The triamcinolone acetonide suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 0.5-1.5 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 50% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate        in the sodium citrate monohydrate and polysorbate-80 solution,        the complete quantity of hyaluronic acid was added, and the        mixture was stirred for 2 hours at moderate speed (to ensure        complete dissolution of the hyaluronic acid).    -   5. Upon complete dissolution of the hyaluronic acid, the total        quantity of chondroitin sulfate was added and the solution of        sodium citrate monohydrate, polysorbate-80, disodium edetate        dihydrate, and hyaluronic acid, and stirred for 2 hours at        moderate speed (to ensure complete dissolution of the        chondroitin sulfate).    -   6. Upon complete dissolution of the chondroitin sulfate, the        resulting solution was autoclaved at 121° C. for 20 min.    -   7. The solution was allowed to cool to room temperature.    -   8. The total required quantity of moxifloxacin hydrochloride was        added to the cooled solution and stirred until completely        dissolved.    -   9. The solution was QS to 65% of the final volume.    -   10. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 5 Moxifloxacin Hydrochloride and Triamcinolone AcetonideOphthalmic Suspension (Multi-Dose)

The composition having Formulation V was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of triamcinolone acetonide was added to        30% of the total required volume of water forming a        triamcinolone acetonide suspension.    -   2. The triamcinolone acetonide suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 0.5-1.5 μm.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 50% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate        in the sodium citrate monohydrate and polysorbate-80 solution,        the complete quantity of hyaluronic acid was added, and the        mixture was stirred for 2 hours at moderate speed (to ensure        complete dissolution of the hyaluronic acid).    -   5. Upon complete dissolution of the hyaluronic acid, the total        quantity of chondroitin sulfate was added and the solution of        sodium citrate monohydrate, polysorbate-80, disodium edetate        dihydrate, and hyaluronic acid, and stirred for 2 hours at        moderate speed (to ensure complete dissolution of the        chondroitin sulfate).    -   6. Upon complete dissolution of the chondroitin sulfate, the        resulting solution was autoclaved at 121° C. for 20 min.    -   7. The solution was allowed to cool to room temperature.    -   8. The total required quantity of moxifloxacin hydrochloride and        total required quantity of benzalkonium chloride were added to        the cooled solution and stirred until completely dissolved.    -   9. The solution was QS to 65% of the final volume.    -   10. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI.

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

EXAMPLES (PREDNISOLONE+MOXIFLOXACIN)

The following ophthalmologically suitableantimicrobial-anti-inflammatory combination formulations of Table 3 weregenerated according to the following procedures.

TABLE 3 Exemplary Formulations. QUANTITY/mL (mg) INGREDIENT Form. IForm. II Form. III Form. IV Prednisolone acetate 10.0-15.0 10.0-15.010.0-15.0 10.0-15.0 (as base) Moxifloxacin HCl (as base) 1.0 1.0 1.0 1.0Polysorbate-80 10.0 10.0 10.0 10.0 Hyaluronic acid  2.0-20.0  2.0-20.0 2.0-20.0  2.0-20.0 Chondroitin sulfate — —  5.0-50.0  5.0-50.0 Sodiumcitrate  1.0-10.0  1.0-10.0  1.0-10.0  1.0-10.0 monohydrate Disodiumedetate dihydrate 1.0-5.0 1.0-5.0 1.0-5.0 1.0-5.0 Benzalkonium chloride— 0.05 — 0.05 Hydrochloric acid/sodium QS to adjust QS to adjust QS toadjust QS to adjust hydroxide pH to 7.0 ± 0.2 pH to 7.0 ± 0.2 pH to 7.0± 0.2 pH to 7.0 ± 0.2 Water QS to 1.0 mL QS to 1.0 mL QS to 1.0 mL QS to1.0 mL (“Form.” = formulation)

Example 1 Moxifloxacin Hydrochloride and Prednisolone Acetate OphthalmicSuspension (Single Dose)

The composition having Formulation I was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of moxifloxacin was added and completely        dissolved.    -   5. Upon completion of the dissolution of moxifloxacin, the total        quantity of hyaluronic acid was added to the completely        dissolved solution of sodium citrate monohydrate,        polysorbate-80, disodium edetate dihydrate, and moxifloxacin and        stirred for 2 hours at moderate speed (to ensure complete        dissolution of the hyaluronic acid).    -   6. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   7. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 2 Moxifloxacin Hydrochloride and Prednisolone Acetate OphthalmicSuspension (Multi Dose)

The composition having Formulation II was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        completely dissolved.    -   5. Upon complete dissolution of the benzalkonium in the sodium        citrate monohydrate, polysorbate-80 solution, and disodium        edetate solution, the complete quantity of moxifloxacin        hydrochloride was added and stirred until completely dissolved.    -   6. Upon complete dissolution of moxifloxacin hydrochloride, the        total quantity of hyaluronic acid was added to the completely        dissolved solution of sodium citrate monohydrate,        polysorbate-80, disodium edetate dihydrate and moxifloxacin        hydrochloride and stirred for 2 hours at moderate speed (to        ensure complete dissolution of the hyaluronic acid).    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 3 Moxifloxacin Hydrochloride and Prednisolone Acetate OphthalmicSuspension (Single Dose)

The composition having Formulation III was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part II:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate        in the sodium citrate monohydrate and polysorbate-80 solution,        the complete quantity of moxifloxacin hydrochloride was added        and stirred until completely dissolved.    -   5. Upon complete dissolution of moxifloxacin hydrochloride, the        total quantity of hyaluronic acid was added to the completely        dissolved solution of sodium citrate monohydrate,        polysorbate-80, disodium edetate dihydrate and moxifloxacin        hydrochloride and stirred for 2 hours at moderate speed (to        ensure complete dissolution of the hyaluronic acid).    -   6. Upon complete dissolution of the hyaluronic acid, the total        quantity of chondroitin sulfate was added and completely        dissolved.    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 4 Moxifloxacin Hydrochloride and Prednisolone Acetate OphthalmicSuspension (Multi Dose)

The composition having Formulation IV was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        allowed to completely dissolve.    -   5. Upon complete dissolution of the benzalkonium chloride, the        total quantity of moxifloxacin was added and allowed to        completely dissolve.    -   6. Upon complete dissolution of the moxifloxacin in the sodium        citrate monohydrate, polysorbate-80 solution, disodium edetate        dihydrate, and benzalkonium chloride solution, the complete        quantity of hyaluronic acid was added, and the mixture was        stirred for 2 hours at moderate speed (to ensure complete        dissolution of the hyaluronic acid).    -   7. Upon complete dissolution of the hyaluronic acid, the total        quantity of chondroitin sulfate was added and the solution of        sodium citrate monohydrate, polysorbate-80, disodium edetate        dihydrate, benzalkonium, and moxifloxacin solution and allowed        to completely dissolve.    -   8. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   9. The solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part TT and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

EXAMPLES (LOTEPREDNOL+MOXIFLOXACIN)

The following ophthalmologically suitableantimicrobial-anti-inflammatory combination formulations of Table 4 weregenerated according to the following procedures.

TABLE 4 Exemplary Formulations. QUANTITY/mL (mg) INGREDIENT Form. IForm. II Form. III Form. IV Loteprednol etabonate 10.0-15.0 10.0-15.010.0-15.0 10.0-15.0 (as base) Moxifloxacin HCl (as base) 1.0 1.0 1.0 1.0Polysorbate-80 10.0 10.0 10.0 10.0 Hyaluronic acid  2.0-20.0  2.0-20.0 2.0-20.0  2.0-20.0 Chondroitin sulfate — —  5.0-50.0  5.0-50.0 Sodiumcitrate  1.0-10.0  1.0-10.0  1.0-10.0  1.0-10.0 monohydrate Disodiumedetate dihydrate 1.0-5.0 1.0-5.0 1.0-5.0 1.0-5.0 Benzalkonium chloride— 0.05 — 0.05 Hydrochloric acid/sodium QS to adjust QS to adjust QS toadjust QS to adjust hydroxide pH to 7.0 ± 0.2 pH to 7.0 ± 0.2 pH to 7.0± 0.2 pH to 7.0 ± 0.2 Water QS to 1.0 mL QS to 1.0 mL QS to 1.0 mL QS to1.0 mL (“Form.” = formulation)

Example 1 Moxifloxacin Hydrochloride and Loteprednol EtabonateOphthalmic Suspension (Single Dose)

The composition having Formulation I was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of loteprednol etabonate was added to 30%        of the total required volume of water forming a loteprednol        etabonate suspension.    -   2. The loteprednol etabonate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of moxifloxacin was added and completely        dissolved.    -   5. Upon completion of the dissolution of moxifloxacin, the total        quantity of hyaluronic acid was added to the completely        dissolved solution of sodium citrate monohydrate,        polysorbate-80, disodium edetate dihydrate, and moxifloxacin and        stirred for 2 hours at moderate speed (to ensure complete        dissolution of the hyaluronic acid).    -   6. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   7. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 2 Moxifloxacin Hydrochloride and Loteprednol EtabonateOphthalmic Suspension (Multi Dose)

The composition having Formulation II was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of loteprednol etabonate was added to 30%        of the total required volume of water forming a loteprednol        etabonate suspension.    -   2. The loteprednol etabonate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        completely dissolved.    -   5. Upon complete dissolution of the benzalkonium in the sodium        citrate monohydrate, polysorbate-80 solution, and disodium        edetate solution, the complete quantity of moxifloxacin        hydrochloride was added and stirred until completely dissolved.    -   6. Upon complete dissolution of moxifloxacin hydrochloride, the        total quantity of hyaluronic acid was added to the completely        dissolved solution of sodium citrate monohydrate,        polysorbate-80, disodium edetate dihydrate and moxifloxacin        hydrochloride and stirred for 2 hours at moderate speed (to        ensure complete dissolution of the hyaluronic acid).    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 3 Moxifloxacin Hydrochloride and Loteprednol EtabonateOphthalmic Suspension (Single Dose)

The composition having Formulation III was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of loteprednol etabonate was added to 30%        of the total required volume of water forming a loteprednol        etabonate suspension.    -   2. The loteprednol etabonate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part II:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate        in the sodium citrate monohydrate and polysorbate-80 solution,        the complete quantity of moxifloxacin hydrochloride was added        and stirred until completely dissolved.    -   5. Upon complete dissolution of moxifloxacin hydrochloride, the        total quantity of hyaluronic acid was added to the completely        dissolved solution of sodium citrate monohydrate,        polysorbate-80, disodium edetate dihydrate and moxifloxacin        hydrochloride and stirred for 2 hours at moderate speed (to        ensure complete dissolution of the hyaluronic acid).    -   6. Upon complete dissolution of the hyaluronic acid, the total        quantity of chondroitin sulfate was added and completely        dissolved.    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 4 Moxifloxacin Hydrochloride and Loteprednol EtabonateOphthalmic Suspension (Multi Dose)

The composition having Formulation IV was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of loteprednol etabonate was added to 30%        of the total required volume of water forming a loteprednol        etabonate suspension.    -   2. The loteprednol etabonate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        allowed to completely dissolve.    -   5. Upon complete dissolution of the benzalkonium chloride, the        total quantity of moxifloxacin was added and allowed to        completely dissolve.    -   5. Upon complete dissolution of the moxifloxacin in the sodium        citrate monohydrate, polysorbate-80 solution, disodium edetate        dihydrate, and benzalkonium chloride solution, the complete        quantity of hyaluronic acid was added, and the mixture was        stirred for 2 hours at moderate speed (to ensure complete        dissolution of the hyaluronic acid).    -   6. Upon complete dissolution of the hyaluronic acid, the total        quantity of chondroitin sulfate was added and the solution of        sodium citrate monohydrate, polysorbate-80, disodium edetate        dihydrate, benzalkonium, and moxifloxacin solution and allowed        to completely dissolve.    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WED).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

EXAMPLES (GATIFLOXACLN+PREDNISOLONIE+BROMFENAC)

The following ophthalmologically suitableantimicrobial-anti-inflammatory combination formulations of Table 5 weregenerated according to the following procedures.

TABLE 5 Exemplary Formulations. QUANTITY/mL (mg) INGREDIENT Form. IForm. II Form. III Form. IV Form. V Form. VI Prednisolone 10.0-15.010.0-15.0 10.0-15.0  10.0-15.0  10.0-15.0 10.0-15.0 acetate (as base)Gatifloxacin (as base) 5.0  5.0  5.0  5.0  5.0  5.0  Bromfenac sodium1.04 1.04 1.04 1.04 1.04 1.04 sesquihydrate Polysorbate-80 10.0   10.0  10.0   10.0   — — Hyaluronic acid  2.0-20.0  2.0-20.0 2.0-20.0 2.0-20.0 2.0-20.0  2.0-20.0 Chondroitin sulfate — — 5.0-50.0 5.0-50.0 — — Sodiumcitrate  1.0-10.0  1.0-10.0 1.0-10.0 1.0-10.0  1.0-10.0  1.0-10.0monohydrate Disodium edetate 1.0-5.0 1.0-5.0 1.0-5.0  1.0-5.0  1.0-5.01.0-5.0 dihydrate Benzalkonium — 0.05 — 0.05 0.05 0.05 chlorideHydrochloric acid/ QS to QS to QS to QS to QS to QS to sodium hydroxideadjust pH adjust pH adjust pH adjust pH adjust pH adjust pH to 7.0 ± 0.2to 7.0 ± 0.2 to 7.0 ± 0.2 to 7.0 ± 0.2 to 7.0 ± 0.2 to 7.0 ± 0.2 WaterQS to 1.0 mL QS to 1.0 mL QS to 1.0 mL QS to 1.0 mL QS to 1.0 mL QS to1.0 mL (“Form.” = formulation)

Example 1 Gatifloxacin, Prednisolone Acetate, and Bromfenac SodiumSesquihydrate Ophthalmic Suspension (Single Dose)

The composition having Formulation I was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part II:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of gatifloxacin was added and completely        dissolved.    -   5. Upon complete dissolution of the gatifloxacin, the total        quantity of bromfenac sodium sesquihydrate was added and        completely dissolved.    -   6. Upon completion of the dissolution of bromfenac sodium        sesquihydrate, the total quantity of hyaluronic acid was added        to the completely dissolved solution of sodium citrate        monohydrate, polysorbate-80, disodium edetate dihydrate,        gatifloxacin, and bromfenac sodium sesquihydrate, and stirred        for 2 hours at moderate speed (to ensure complete dissolution of        the hyaluronic acid).    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 2 Gatifloxacin, Prednisolone Acetate, and Bromfenac SodiumSesquihydrate Ophthalmic Suspension (Multi-Dose)

The composition having Formulation II was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part II:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        completely dissolved.    -   5. Upon complete dissolution of the benzalkonium in the sodium        citrate monohydrate, polysorbate-80 solution, and disodium        edetate solution, the total quantity of gatifloxacin was added        and allowed to completely dissolve.    -   6. Upon the complete dissolution of the gatifloxacin, the total        quantity of bromfenac sodium sesquihydrate was added and allowed        to completely dissolve.    -   7. Upon complete dissolution of bromfenac sodium sesquihydrate,        the total quantity of hyaluronic acid was added to the        completely dissolved solution of sodium citrate monohydrate,        polysorbate-80, disodium edetate dihydrate, gatifloxacin, and        bromfenac sodium sesquihydrate and stirred for 2 hours at        moderate speed (to ensure complete dissolution of the hyaluronic        acid).    -   8. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   9. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 3 Gatifloxacin, Prednisolone Acetate, and Bromfenac SodiumSesquihydrate Ophthalmic Suspension (Single Dose)

The composition having Formulation III was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate        in the sodium citrate monohydrate and polysorbate-80 solution,        the complete quantity of gatifloxacin was added and stirred        until completely dissolved.    -   5. Upon complete dissolution of moxifloxacin hydrochloride, the        total quantity of hyaluronic acid was added to the completely        dissolved solution of sodium citrate monohydrate,        polysorbate-80, disodium edetate dihydrate and gatifloxacin and        stirred for 2 hours at moderate speed (to ensure complete        dissolution of the hyaluronic acid).    -   6. Upon complete dissolution of the hyaluronic acid, the total        quantity of chondroitin sulfate was added and completely        dissolved.    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part TT and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Example 4 Gatifloxacin, Prednisolone Acetate, and Bromfenac SodiumSesquihydrate Ophthalmic Suspension (Multi-Dose)

The composition having Formulation IV was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        allowed to completely dissolve.    -   5. Upon complete dissolution of the benzalkonium chloride, the        total quantity of gatifloxacin was added and allowed to        completely dissolve.    -   6. Upon the complete dissolution of gatifloxacin, the total        quantity of bromfenac sodium sesquihydrate was added and allowed        to completely dissolve.    -   7. Upon complete dissolution of the bromfenac sodium        sesquihydrate in the sodium citrate monohydrate, polysorbate-80        solution, disodium edetate dihydrate, benzalkonium chloride, and        gatifloxacin solution, the complete quantity of hyaluronic acid        was added, and the mixture was stirred for 2 hours at moderate        speed (to ensure complete dissolution of the hyaluronic acid).    -   8. Upon complete dissolution of the hyaluronic acid, the total        quantity of chondroitin sulfate was added and the solution of        sodium citrate monohydrate, polysorbate-80, disodium edetate        dihydrate, benzalkonium, and moxifloxacin solution and allowed        to completely dissolve.    -   9. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   10. The solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 5 Gatifloxacin, Prednisolone Acetate, and Bromfenac SodiumSesquihydrate Ophthalmic Suspension (Single Dose)

The composition having Formulation V was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part II:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of disodium edetate dihydrate was added to        the completely dissolved solution of sodium citrate monohydrate        and completely dissolved.    -   3. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        completely dissolved.    -   4. Upon complete dissolution of the benzalkonium in the sodium        citrate monohydrate and disodium edetate solution, the total        quantity of gatifloxacin was added and allowed to completely        dissolve.    -   5. Upon the complete dissolution of the gatifloxacin, the total        quantity of bromfenac sodium sesquihydrate was added and allowed        to completely dissolve.    -   6. Upon complete dissolution of bromfenac sodium sesquihydrate,        the total quantity of hyaluronic acid was added to the        completely dissolved solution of sodium citrate monohydrate,        disodium edetate dihydrate, gatifloxacin, and bromfenac sodium        sesquihydrate and stirred for 2 hours at moderate speed (to        ensure complete dissolution of the hyaluronic acid).    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 6

Gatifloxacin, prednisolone acetate, and bromfenac sodium sesquihydrateophthalmic suspension (multi dose)

The composition having Formulation V was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of disodium edetate dihydrate was added to        the completely dissolved solution of sodium citrate monohydrate        and completely dissolved.    -   3. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        completely dissolved.    -   4. Upon complete dissolution of the benzalkonium in the sodium        citrate monohydrate and disodium edetate solution, the total        quantity of gatifloxacin was added and allowed to completely        dissolve.    -   5. Upon the complete dissolution of the gatifloxacin, the total        quantity of bromfenac sodium sesquihydrate was added and allowed        to completely dissolve.    -   6. Upon complete dissolution of bromfenac sodium sesquihydrate,        the total quantity of hyaluronic acid was added to the        completely dissolved solution of sodium citrate monohydrate,        disodium edetate dihydrate, gatifloxacin, and bromfenac sodium        sesquihydrate and stirred for 2 hours at moderate speed (to        ensure complete dissolution of the hyaluronic acid).    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part (i.e., the Part composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WED.

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

EXAMPLES (MOXIFLOXACLN+PREDNISOLONIE+BROMFENAC)

The following ophthalmologically suitableantimicrobial-anti-inflammatory combination formulations of Table 6 weregenerated according to the following procedures.

TABLE 6 Exemplary Formulations. QUANTITY/mL (mg) INGREDIENT Form. IForm. II Form. III Form. IV Form. V Form. VI Prednisolone 10.0-15.010.0-15.0 10.0-15.0 10.0-15.0 10.0-15.0 10.0-15.0 acetate (as base)Moxifloxacin 5.0 5.0 5.0 5.0 5.0 5.0 hydrochloride (as base) Bromfenacsodium 1.04 1.04 1.04 1.04 1.04 1.04 sesquihydrate Polysorbate-80 10.010.0 10.0 10.0 — — Hyaluronic acid  2.0-20.0  2.0-20.0  2.0-20.0 2.0-20.0  2.0-20.0  2.0-20.0 Chondroitin — —  5.0-50.0  5.0-50.0 — —sulfate Sodium citrate  1.0-10.0  1.0-10.0  1.0-10.0  1.0-10.0  1.0-10.0 1.0-10.0 monohydrate Disodium edetate 1.0-5.0 1.0-5.0 1.0-5.0 1.0-5.01.0-5.0 1.0-5.0 dihydrate Benzalkonium — 0.05 — 0.05 0.05 0.05 chlorideHydrochloric QS to QS to QS to QS to QS to QS to acid/sodium adjust pHadjust pH adjust pH adjust pH adjust pH adjust pH hydroxide to 7.0 ± 0.2to 7.0 ± 0.2 to 7.0 ± 0.2 to 7.0 ± 0.2 to 7.0 ± 0.2 to 7.0 ± 0.2 WaterQS to 1.0 QS to 1.0 QS to 1.0 QS to 1.0 QS to 1.0 QS to 1.0 mL mL mL mLmL mL (″Form.″ = formulation)

Example 1 Moxifloxacin Hydrochloride, Prednisolone Acetate, andBromfenac Sodium Sesquihydrate Ophthalmic Suspension (Single Dose)

The composition having Formulation I was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part II:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of moxifloxacin hydrochloride was added and        completely dissolved.    -   5. Upon complete dissolution of the moxifloxacin hydrochloride,        the total quantity of bromfenac sodium sesquihydrate was added        and completely dissolved.    -   6. Upon completion of the dissolution of bromfenac sodium        sesquihydrate, the total quantity of hyaluronic acid was added        to the completely dissolved solution of sodium citrate        monohydrate, polysorbate-80, disodium edetate dihydrate,        moxifloxacin hydrochloride, and bromfenac sodium sesquihydrate,        and stirred for 2 hours at moderate speed (to ensure complete        dissolution of the hyaluronic acid).    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 2 Moxifloxacin Hydrochloride, Prednisolone Acetate, andBromfenac Sodium Sesquihydrate Ophthalmic Suspension (Multi-Dose)

The composition having Formulation II was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part II:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        completely dissolved.    -   5. Upon complete dissolution of the benzalkonium in the sodium        citrate monohydrate, polysorbate-80 solution, and disodium        edetate solution, the total quantity of moxifloxacin        hydrochloride was added and allowed to completely dissolve.    -   6. Upon the complete dissolution of the moxifloxacin        hydrochloride, the total quantity of bromfenac sodium        sesquihydrate was added and allowed to completely dissolve.    -   7. Upon complete dissolution of bromfenac sodium sesquihydrate,        the total quantity of hyaluronic acid was added to the        completely dissolved solution of sodium citrate monohydrate,        polysorbate-80, disodium edetate dihydrate, moxifloxacin        hydrochloride, and bromfenac sodium sesquihydrate and stirred        for 2 hours at moderate speed (to ensure complete dissolution of        the hyaluronic acid).    -   8. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   9. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (above) was sterile filtered into Part I (above)        through a 0.2 μm filter 2. The remaining 5% of the total volume        of water was used to rinse the container of Part II and this was        passed through the same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 3 Moxifloxacin Hydrochloride, Prednisolone Acetate, andBromfenac Sodium Sesquihydrate Ophthalmic Suspension (Single Dose)

The composition having Formulation III was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate        in the sodium citrate monohydrate and polysorbate-80 solution,        the complete quantity of moxifloxacin hydrochloride was added        and stirred until completely dissolved.    -   5. Upon complete dissolution of moxifloxacin hydrochloride, the        total quantity of hyaluronic acid was added to the completely        dissolved solution of sodium citrate monohydrate,        polysorbate-80, disodium edetate dihydrate and moxifloxacin        hydrochloride and stirred for 2 hours at moderate speed (to        ensure complete dissolution of the hyaluronic acid).    -   6. Upon complete dissolution of the hyaluronic acid, the total        quantity of chondroitin sulfate was added and completely        dissolved.    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 4 Moxifloxacin Hydrochloride, Prednisolone Acetate, andBromfenac Sodium Sesquihydrate Ophthalmic Suspension (Multi-Dose)

The composition having Formulation IV was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of polysorbate-80 was added to the completely        dissolved solution of sodium citrate monohydrate and completely        dissolved.    -   3. Upon complete dissolution of the polysorbate-80, disodium        edetate dihydrate was added to the completely dissolved solution        of sodium citrate monohydrate and polysorbate-80 and completely        dissolved.    -   4. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        allowed to completely dissolve.    -   5. Upon complete dissolution of the benzalkonium chloride, the        total quantity of gatifloxacin was added and allowed to        completely dissolve.    -   6. Upon the complete dissolution of moxifloxacin hydrochloride,        the total quantity of bromfenac sodium sesquihydrate was added        and allowed to completely dissolve.    -   7. Upon complete dissolution of the bromfenac sodium        sesquihydrate in the sodium citrate monohydrate, polysorbate-80        solution, disodium edetate dihydrate, benzalkonium chloride, and        moxifloxacin hydrochloride solution, the complete quantity of        hyaluronic acid was added, and the mixture was stirred for 2        hours at moderate speed (to ensure complete dissolution of the        hyaluronic acid).    -   8. Upon complete dissolution of the hyaluronic acid, the total        quantity of chondroitin sulfate was added and the solution of        sodium citrate monohydrate, polysorbate-80, disodium edetate        dihydrate, benzalkonium, and moxifloxacin solution and allowed        to completely dissolve.    -   9. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   10. The solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (above) was sterile filtered into Part I (above)        through a 0.2 μm filter 2. The remaining 5% of the total volume        of water was used to rinse the container of Part II and this was        passed through the same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 5 Moxifloxacin Hydrochloride, Prednisolone Acetate, andBromfenac Sodium Sesquihydrate Ophthalmic Suspension (Single Dose)

The composition having Formulation V was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of disodium edetate dihydrate was added to        the completely dissolved solution of sodium citrate monohydrate        and completely dissolved.    -   3. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        completely dissolved.    -   4. Upon complete dissolution of the benzalkonium in the sodium        citrate monohydrate and disodium edetate solution, the total        quantity of moxifloxacin hydrochloride was added and allowed to        completely dissolve.    -   5. Upon the complete dissolution of the moxifloxacin        hydrochloride, the total quantity of bromfenac sodium        sesquihydrate was added and allowed to completely dissolve.    -   6. Upon complete dissolution of bromfenac sodium sesquihydrate,        the total quantity of hyaluronic acid was added to the        completely dissolved solution of sodium citrate monohydrate,        disodium edetate dihydrate, moxifloxacin hydrochloride, and        bromfenac sodium sesquihydrate and stirred for 2 hours at        moderate speed (to ensure complete dissolution of the hyaluronic        acid).    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part TT and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

Example 6 Moxifloxacin, Prednisolone Acetate, and Bromfenac SodiumSesquihydrate Ophthalmic Suspension (Multi Dose)

The composition having Formulation V was manufactured according to thefollowing process.

Part I:

-   -   1. The total quantity of prednisolone acetate was added to 30%        of the total required volume of water forming a prednisolone        acetate suspension.    -   2. The prednisolone acetate suspension was passed through a        homogenizer to form a suspension of particles having a D₅₀        particle size of 2-3 m.    -   3. The resulting suspension was sterilized by autoclaving at        121° C. for 30 min.    -   4. The sterilized solution was constantly stirred while being        allowed to cool.

Part I:

-   -   1. The total quantity of sodium citrate monohydrate was        completely dissolved in 55% of the total required water.    -   2. Upon complete dissolution of the sodium citrate monohydrate,        the total quantity of disodium edetate dihydrate was added to        the completely dissolved solution of sodium citrate monohydrate        and completely dissolved.    -   3. Upon complete dissolution of the disodium edetate dihydrate,        the total quantity of benzalkonium chloride was added and        completely dissolved.    -   4. Upon complete dissolution of the benzalkonium in the sodium        citrate monohydrate and disodium edetate solution, the total        quantity of moxifloxacin hydrochloride was added and allowed to        completely dissolve.    -   5. Upon the complete dissolution of the moxifloxacin        hydrochloride, the total quantity of bromfenac sodium        sesquihydrate was added and allowed to completely dissolve.    -   6. Upon complete dissolution of bromfenac sodium sesquihydrate,        the total quantity of hyaluronic acid was added to the        completely dissolved solution of sodium citrate monohydrate,        disodium edetate dihydrate, moxifloxacin hydrochloride, and        bromfenac sodium sesquihydrate and stirred for 2 hours at        moderate speed (to ensure complete dissolution of the hyaluronic        acid).    -   7. The pH was adjusted using pH adjusting agents (HCl and NaOH)        to 7.0±0.2.    -   8. The resulting solution was QS to 65% of the final volume.

Part III

-   -   1. Part II (i.e., the Part II composition, described above) was        sterile filtered into Part I (i.e., the Part I composition,        described above) through a 0.2 μm filter.    -   2. The remaining 5% of the total volume of water was used to        rinse the container of Part II and this was passed through the        same 0.2 μm filter.    -   3. The final solution was QS to a final volume with additional        sterile-filtered water for injection (WFI).

Composition(s) exemplified in this Example are expected to be stableover relevant periods of storage under typical conditions and to beophthalmologically suitable and when provided in therapeuticallyeffective amounts over a suitable treatment protocol effective attreating one or more bacterial conditions.

The invention claimed is:
 1. An ophthalmologically suitablepharmaceutical composition in the form of a suspension comprising: (a)an effective amount of at least one ionic suspension agent; (b) aneffective amount of at least one non-ionic suspension agent; (c) atleast two pharmaceutical ingredients comprising (1) moxifloxacin or apharmaceutically acceptable salt thereof in a range of about 0.01% toabout 0.5% by weight, and (2) loteprednol or a pharmaceuticallyacceptable salt thereof in a range of about 0.1% to about 5% by weight;and (d) an effective amount of a pharmaceutically acceptable chelatingagent.
 2. The composition of claim 1, wherein one or more of the atleast one ionic suspension agents in the composition is not capable ofsignificantly increasing the solubilization of any of the at least twopharmaceutical ingredients.
 3. The composition of claim 2, wherein thecomposition comprises only a single ionic suspension agent.
 4. Thecomposition of claim 1, wherein at least one non-ionic suspension agentin the composition is also a non-ionic surfactant.
 5. The composition ofclaim 4, wherein the non-ionic surfactant comprises an effective amountof a polysorbate, a polyoxyl-ethylated castor oil, or a combinationthereof.
 6. The composition of claim 1, wherein the ratio ofmoxifloxacin or pharmaceutically acceptable salt thereof to thecombination of the at least one ionic suspension agent and the at leastone non-ionic suspension agent is about 1:10 to about 1:32.
 7. Thecomposition of claim 1, wherein the ratio of the at least one ionicsuspension agent to the at least one non-ionic suspension agent is about1:8 to about 4:1.
 8. The composition of claim 1, wherein thepharmaceutically acceptable chelating agent is disodium edetate in aconcentration of about 0.1 mg/mL to about 0.5 mg/mL.
 9. The compositionof claim 1, wherein the at least one ionic suspension agent comprises aneffective amount of a hyaluronic acid, carboxymethylcellulose, acaciagum, or a mixture of any or all thereof.
 10. The composition of claim 9,wherein the at least one ionic suspension agent is mostly composed of ahyaluronic acid component.
 11. The composition of claim 10, wherein thecomposition comprises hyaluronic acid in a concentration of about 2mg/mL to about 20 mg/mL.
 12. The composition of claim 11, wherein theaverage molecular weight of most of the hyaluronic acid in thecomposition is about 360 kDa to about 1200 kDa.
 13. The composition ofclaim 11, wherein the composition further comprises chondroitin sulfatein a concentration of about 5 mg/mL to about 50 mg/mL.
 14. Thecomposition of claim 1, wherein (a) the concentration of moxifloxacin orpharmaceutically acceptable salt thereof is about 0.1% by weight, (b)the concentration of loteprednol or pharmaceutically acceptable saltthereof is about 1.5% by weight, or (c) the concentration ofmoxifloxacin or pharmaceutically acceptable salt thereof is about 0.1%by weight and the concentration of loteprednol or pharmaceuticallyacceptable salt thereof is about 1.5% by weight.
 15. The composition ofclaim 1, wherein the osmolality of the composition is about 200 mOsm/kgto about 350 mOsm/kg.
 16. The composition of claim 5, wherein thenon-ionic surfactant comprises an effective amount of polysorbate 80.17. The composition of claim 16, wherein the polysorbate 80 is presentin the composition in a concentration of about 5 mg/mL to about 15mg/mL.
 18. The composition of claim 1, wherein the composition comprisesan effective amount of a polyoxyl-ethylated castor oil solubilizingagent.
 19. The composition of claim 18, wherein the polyoxyl-ethylatedcastor oil solubilizing agent is present in an amount of about 0.1% toabout 1% by weight.
 20. The composition of claim 1, wherein thepharmaceutically acceptable chelating agent is a chelating agent whichresults in a significantly similar or improved stability of themoxifloxacin or pharmaceutically acceptable salt thereof or loteprednolor pharmaceutically acceptable salt thereof as compared to disodiumedetate in a concentration of about 0.1 mg/mL to about 0.5 mg/mL. 21.The composition of claim 1, wherein the composition is formulated fortopical administration and is contained in a device adapted for deliveryby drops to the eye.
 22. A method of treating or preventing an ocularbacterial infection in a mammalian eye comprising administering to themammalian eye an effective amount of an ophthalmologically suitablecomposition comprising: (a) an effective amount of at least one ionicsuspension agent wherein at least one of the at least one ionicsuspension agents is not a solubilizing agent; (b) an effective amountof at least one non-ionic suspension agent; (c) at least twopharmaceutical ingredients comprising (1) moxifloxacin or apharmaceutically acceptable salt thereof in a range of about 0.01% toabout 0.5% by weight, and (2) loteprednol or a pharmaceuticallyacceptable salt thereof in a range of about 0.1% to about 5% by weight;and (d) an effective amount of a pharmaceutically acceptable chelatingagent, wherein the composition does not comprise any block copolymer ofpoly(ethylene oxide) and poly(propylene oxide).
 23. The method of claim22, wherein the composition comprises only a single ionic suspensionagent.
 24. The method of claim 22, wherein at least one non-ionicsuspension agent of the composition is also a non-ionic surfactant. 25.The method of claim 24, wherein the at least one non-ionic surfactantcomprises an effective amount of a polysorbate, a polyoxyl-ethylatedcastor oil, or a combination thereof.
 26. The method of claim 22,wherein the ratio of moxifloxacin or pharmaceutically acceptable saltthereof to the combination of the at least one ionic suspension agentand the least one non-ionic suspension agent is about 1:10 to about 1:32and the ratio of the at least one ionic suspension agent to the at leastone non-ionic suspension agent is about 1:8 to about 4:1.
 27. The methodof claim 22, wherein the at least one ionic suspension agent comprisesan effective amount of a hyaluronic acid, carboxymethylcellulose, acaciagum, or a mixture of any or all thereof.
 28. The method of claim 27,wherein the at least one ionic suspension agent is mostly composed of ahyaluronic acid component with an average molecular weight of about 360kDa to about 1200 kDa.
 29. The method of claim 28, wherein thecomposition comprises hyaluronic acid in a concentration of about 2mg/mL to about 20 mg/mL.
 30. The method of claim 22, wherein theconcentration of moxifloxacin or pharmaceutically acceptable saltthereof in the composition is about 0.1% by weight; the concentration ofloteprednol or pharmaceutically acceptable salt thereof in thecomposition is about 1.5% by weight; or the concentration ofmoxifloxacin or pharmaceutically acceptable salt thereof in thecomposition is about 0.1% by weight and the concentration of loteprednolor pharmaceutically acceptable salt thereof in the composition is about1.5% by weight.
 31. The method of claim 25, wherein the non-ionicsurfactant in the composition comprises polysorbate 80 in aconcentration of about 5 mg/mL to about 15 mg/mL or a polyoxyl-ethylatedcastor oil in an amount of about 0.1% to about 1% by weight.